Bcl-2 inhibitors

ABSTRACT

The disclosure includes compounds of Formula (A):wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, and R12, j, k, m, n, Y, W, W1, W2, W3, V, L, Z1, Q1, Q2, Q3, and Q4, are defined herein. Also disclosed is a method for treating a neoplastic disease, an autoimmune disease, or a neorodegenerative disease with these compounds.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.16/795,720, filed Feb. 20, 2020, which is a continuation ofInternational Patent Application No.: PCT/US2018/047444, filed on Aug.22, 2018, which claims the benefit of the filing date of U.S.Provisional Application No. 62/549,081, filed on Aug. 23, 2017; and U.S.Provisional Application No. 62/615,007, filed on Jan. 9, 2018. Theentire contents of each of the aforementioned applications areincorporated herein by reference.

BACKGROUND OF THE INVENTION

Apoptosis, or programmed cell death, is a conserved and regulatedprocess that is the primary mechanism for the removal of aged, damagedand unnecessary cells. The ability to block apoptotic signaling is a keyhallmark of cancer and is thus important for oncogenesis, tumormaintenance and chemoresistance [Hanahan, D. & Weinberg, R. A. Thehallmarks of cancer. Cell 100, 57-70 (2000).]. Dynamic bindinginteractions between prodeath (for example, BCL-2-associated X protein(BAX), BCL-2 antagonist/killer 1 (BAK), BCL-2-associated agonist of celldeath (BAD), BCL-2-like 11 (BIM), NOXA and BCL-2 binding component 3(PUMA)) and prosurvival (BCL-2, BCL-XL, BCL-2-like 2 (BCL-W), myeloidcell leukemia sequence 1 (MCL-1) and BCL-2-related protein A1 (BFL-1))proteins in the BCL-2 family control commitment to programmed celldeath. Altering the balance among these opposing factions provides onemeans by which cancer cells undermine normal apoptosis and gain asurvival advantage [Youle, R. J. & Strasser, A. The BCL-2 proteinfamily: opposing activities that mediate cell death. Nat. Rev. Mol. CellBiol. 9, 47-59 (2008)].

BCL-2, the first identified apoptotic regulator, was originally clonedfrom the breakpoint of a t(14;18) translocation present in human B celllymphomas [Tsujimoto, Y., et al. Science 228, 1440-1443 (1985); Cleary,M. L., et al Cell 47, 19-28 (1986); Boise, L. H. et al. Cell 74, 597-608(1993)]. This protein has since been shown to have a dominant role inthe survival of multiple lymphoid malignancies [Vaux, D. L., et al pre-Bcells. Nature 335, 440-442 (1988)]. Overexpression of Bcl-2 proteinscorrelates with resistance to chemotherapy, clinical outcome, diseaseprogression, overall prognosis or a combination thereof in variouscancers and disorders of the immune system. Involvement of Bcl-2proteins in bladder cancer, brain cancer, breast cancer, bone marrowcancer, cervical cancer, chronic lymphocytic leukemia, colorectalcancer, esophageal cancer, hepatocellular cancer, lymphoblasticleukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cellorigin, melanoma, myelogenous leukemia, myeloma, oral cancer, ovariancancer, non-small cell lung cancer, prostate cancer, small cell lungcancer, spleen cancer, and the like is described in PCT US 2004/36770,published as WO 2005/049593, and PCT US 2004/37911, published as WO2005/024636. Involvement of Bcl-2 proteins in immune and autoimmunediseases is described in Current Allergy and Asthma Reports 2003, 3,378-384; British Journal of Hematology 2000, 110(3), 584-90; Blood 2000,95(4), 1283-92; and New England Journal of Medicine 2004, 351(14),1409-1418. Involvement of Bcl-2 proteins in arthritis is disclosed in WO2009/064938. Involvement of Bcl-2 proteins in bone marrow transplantrejection is disclosed in US 2008-0182845 A1. All incorporated herein byreference.

In the last decade, several Bcl-2 inhibitors such as ABT-737, ABT-263,and ABT-199 as shown below have been identified and entered humanclinical trials for cancers treatment.

ABT-737 is discovered by nuclear magnetic resonance (NMR)-basedscreening, parallel synthesis and structure based fragment drug design[Tillman Oltersdorf, et al, Nature, Vol 435, 2005, p 677]. ABT-737 asmall-molecule inhibitor of the anti-apoptotic proteins Bcl-2, Bcl-XLand Bcl-w, with an affinity two to three orders of magnitude more potentthan previously reported compounds. Mechanistic studies reveal thatABT-737 does not directly initiate the apoptotic process, but enhancesthe effects of death signals, displaying synergistic cytotoxicity withchemotherapeutics and radiation. ABT-737 exhibitssingle-agent-mechanism-based killing of cells from lymphoma andsmall-cell lung carcinoma lines, as well as primary patient-derivedcells, and in animal models, ABT-737 improves survival, causesregression of established tumors, and produces cures in a highpercentage of the mice. Unfortunately, ABT-737 is not orallybioavailable, and its formulation for intravenous delivery is hamperedby its low aqueous solubility.

After extensive MedChem effort, an orally bioavailable Bcl-2 inhibitorABT-263 (Navitoclax) has been developed [Cheol-Min Park, et al J. Med.Chem. 2008, 51, 6902-6915]. ABT-263 is a potent inhibitor of Bcl-xL,Bcl-2 and Bcl-w with Ki of ≤0.5 nM, ≤1 nM and ≤1 nM. ABT-263 has an IC₅₀of 110 nM against SCLC H146 cell line. When ABT-263 is administered at100 mg/kg/day in the H345 xenograft model, significant antitumorefficacy is observed with 80% TGI and 20% of treated tumors indicatingat least a 50% reduction in tumor volume. Oral administration of ABT-263alone causes complete tumor regressions in xenograft models ofsmall-cell lung cancer and acute lymphoblastic leukemia [Tse C, et al.Cancer Res. 2008, 68(9), 3421-3428]. In the clinical trial, however, theinhibition of BCL-XL by ABT-263 (navitoclax) induces a rapid,concentration-dependent decrease in the number of circulating platelets.This mechanism-based thrombocytopenia is the dose-limiting toxicity ofsingle-agent navitoclax treatment in patients and limits the ability todrive drug concentrations into a highly efficacious range.

Thus, a BCL-2 selective (BCL-XL sparing) inhibitor would culminate insubstantially reduced thrombocytopenia while maintaining efficacy inlymphoid malignancies. The resulting increase in the therapeutic windowshould allow for greater BCL-2 suppression and clinical efficacy inBCL-2-dependent tumor types. After extensive MedChem, ABT-199 (GDC-0199)has been successfully developed [Andrew J Souers, et al, NatureMedicine, Volume 19, 22, p 202, 2013]. ABT-199 is a Bcl-2-selectiveinhibitor with Ki of <0.01 nM, >4800-fold more selective versus Bcl-xLand Bcl-w, and no activity to Mcl-1. ABT-199 potently inhibits RS4;11cells with EC₅₀ of 8 nM. In addition, ABT-199 induces a rapid apoptosisin RS4;11 cells with cytochrome c release, caspase activation, and theaccumulation of sub-G0/G1 DNA. Quantitative immunoblotting reveals thatsensitivity to ABT-199 correlated strongly with the expression of Bcl-2,including NHL, DLBCL, MCL, AML and ALL cell lines. ABT-199 also inducesapoptosis in CLL with an average EC₅₀ of 3.0 nM. A single dose of 100mg/kg of ABT-199 causes a maximal tumor growth inhibition of 95% andtumor growth delay of 152% in RS4;11 xenografts. ABT-199 also inhibitsxenograft growth (DoHH2, Granta-519) as a single agent or in combinationwith Bendamustine and other agents. Human Phase I and II data showedthat ABT-199 is highly efficacious for CLL who have 17p deletion, andwas approved by FDA in 2016.

WO/2017/132474 discloses a novel class of BCL-2 inhibitors. However,there is still a strong need for continuing search in this field of artfor more potent BCL-2 inhibitor.

SUMMARY OF THE INVENTION

In a first embodiment, this invention provides compounds of the Formula(A) or an N-oxide thereof, or a pharmaceutically acceptable salt,solvate, polymorph, tautomer, stereoisomer, an isotopic form, or aprodrug of said compound of Formula (A) or N-oxide thereof:

wherein

Q₁ is a 6-membered heterocycloalkyl, 6-membered heterocycloalkenyl, or6-membered heteroaryl;

Q₂ is an aryl, or heteroaryl;

Q₃ is a cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl,aryl, or heteroaryl;

Q₄ is

each of R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, and R₁₂,independently, is H, D, alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl,halo, nitro, oxo, cyano, OR_(a), SR_(a), alkyl-R_(a), NH(CH₂)_(p)R_(a),C(O)R_(a), S(O)R_(a), SO₂R_(a), C(O)OR_(a), OC(O)R_(a), NR_(b)R_(c),P(O)R_(b)R_(c), alkyl-P(O)R_(b)R_(c), C(O)N(R_(b))R_(c),N(R_(b))C(O)R_(c), S(O)(═N(R_(a)))R_(b), —N═S(O)R_(b)R_(c),SO₂N(R_(b))R_(c), or N(R_(b))SO₂R_(c), in which said cycloalkyl,cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl isoptionally substituted with one or more R_(d);

R_(a), R_(b), R_(c) and R_(d), independently, is H, D, alkyl, alkenyl,alkynyl, halo, cyano, amine, nitro, hydroxy, C(O)NHOH, C(O)OH, C(O)NH₂,alkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl,alkoxycarbonyl, alkylcarbonylamino, alkylamino, oxo, halo-alkylamino,cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, orheteroaryl, in which said alkyl, cycloalkyl, cycloalkenyl,heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl is optionallysubstituted with one or more R_(e);

R_(e) is H, D, alkyl, alkenyl, alkynyl, halo, cyano, amine, nitro,hydroxy, C(O)NHOH, alkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl,aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylcarbonylamino,alkylamino, oxo, halo-alkylamino, cycloalkyl, cycloalkenyl,heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl;

Z₁ is a bond, (CH₂)_(p), N(H), O, S, C(O), S(O₂), OC(O), C(O)O, OSO₂,S(O₂)O, C(O)S, SC(O), C(O)C(O), C(O)N(H), N(H)C(O), S(O₂)N(H),N(H)S(O₂), OC(O)O, OC(O)S, OC(O)N(H), N(H)C(O)O, N(H)C(O)S,N(H)C(O)N(H), (CH₂)_(p)N(H)(CH₂)_(q), (CH₂)_(p)N(H)C(O)(CH₂)_(q),(CH₂)_(p)C(O)N(H)(CH₂)_(q), OC(O)N(H)(CH₂)_(p+1)N(H)(CH₂)_(q), abivalent alkenyl group, or a bivalent alkynyl group;

L is a bond, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl, in which saidalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl,aryl, or heteroaryl is optionally substituted with one or more R_(d);

each of Y, W, and W₂, independently, is CH or N;

W₁ is N;

W₃ is O or N(R_(a));

V is N, C, or CH;

two of R₉ group, taken together with the atom to which they areattached, may optionally form a cycloalkyl or heterocycloalkyl, in whichsaid cycloalkyl or heterocycloalkyl of R₉ is optionally substituted withone or more R_(d);

two of R₂ group, taken together with the atom to which they areattached, may optionally form a cycloalkyl or heterocycloalkyl, in whichsaid cycloalkyl or heterocycloalkyl of R₂ is optionally substituted withone or more R_(d);

two of R₁₀ group, taken together with the atom to which they areattached, may optionally form a cycloalkyl or heterocycloalkyl, in whichsaid cycloalkyl or heterocycloalkyl of R₁₀ is optionally substitutedwith one or more R_(d);

R₁₁ and R₁₂ group, taken together with the atom to which they areattached, may optionally form a cycloalkyl or heterocycloalkyl, in whichsaid cycloalkyl or heterocycloalkyl of R₁₁ or R₁₂ is optionallysubstituted with one or more R_(d);

R₁₀ and R₂ group, taken together with the atom to which they areattached, may optionally form a cycloalkyl or heterocycloalkyl, in whichsaid cycloalkyl or heterocycloalkyl of R₁₀ or R₂ is optionallysubstituted with one or more R_(d);

R₄ and —Z₁-L-R₆ group, taken together with the atom to which they areattached, may optionally form a cycloalkyl, cycloalkenyl,heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl, in which saidcycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, orheteroaryl of R₄ is optionally substituted with one or more R_(d);

R_(b) and R_(c) group, taken together with the atom to which they areattached, may optionally form a cycloalkyl, or heterocycloalkyl, inwhich said cycloalkyl or heterocycloalkyl of R_(b) and R_(c), isoptionally substituted with one or more R;

two of R_(d) group, taken together with the atom to which they areattached, may optionally form a cycloalkyl, or heterocycloalkyl, inwhich said cycloalkyl or heterocycloalkyl of R_(d) is optionallysubstituted with one or more R_(e);

two of R_(e) group, taken together with the atom to which they areattached, may optionally form a cycloalkyl, or heterocycloalkyl;

each of j and k, independently, is 0, 1, 2, 3, 4, 5, 6, 7, or 8; and

each of m, n, p, q, and r, independently, is 0, 1, 2, 3, or 4;

optionally, provided that when

then —Z₁-L-R₆ is not

In a second embodiment, the invention provides a compound represented byFormula (B), wherein Z₂ is —O—, —CH₂, —C(O), —N(R_(a))—, —S—, —S(O)—,—S(O₂)—, —S(O)(═N(R_(a)))—, or —P(O)(R_(a))—; and A is —C(R₂R₂)_(r), or—O—:

or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate,polymorph, tautomer, stereoisomer, an isotopic form, or a prodrug ofsaid compound of Formula (B) or N-oxide thereof, wherein

Z₂ is —O—, —CH₂—, —C(O)—, —N(R_(a))—, —S—, —S(O)—, —S(O₂)—,—S(O)(═N(R_(a)))—, —P(O)(R_(a))—; wherein R_(a) of Z₂, independently, isH, D, C₁-C₆alkyl, C₂-C₆alkenyl, C₁-C₆alkylcarbonyl, C₁-C₆alkoxycarbonyl,C₃-C₆cycloalkyl, 5-8 membered monocyclic heterocycloalkyl, C₆-C₁₄aryl,or 5-8 membered monocyclicheteroaryl, in which said C₁-C₆alkyl,C₃-C₆cycloalkyl, 5-8 membered monocyclic heterocycloalkyl, C₆-C₁₄aryl,5-8 membered monocyclic heteroaryl is optionally substituted with one ormore Re, and

A is —(CR₂R₂)_(r)— or —O—; wherein r is 0, 1, 2, or 3;

-   -   each R₂ independently is H, —(C₁-C₄)alkoxy, —(C₁-C₄)alkyl        optionally substituted with —(C₁-C₄)alkoxy, or    -   two of R₂ groups, taken together with the same carbon atom to        which they are attached, form —(C₃-C₆)cycloalkyl or 4-6 membered        heterocyclic ring, wherein the —(C₃-C₆)cycloalkyl or 4-6        membered heterocyclic ring is optionally substituted with        —(C₁-C₄)alkyl, —(C₁-C₄)haloalkyl or oxetanyl; and the remaining        variables are as defined in the first embodiment.

In a third embodiment, the invention provides a compound represented byFormula (C):

or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate,polymorph, tautomer, stereoisomer, an isotopic form, or a prodrug ofsaid compound of Formula (C) or N-oxide thereof, wherein R₁ is H, D,halo or —(C₁-C₄)alkyl, and the remaining variables are as defined in thefirst and/or second embodiments.

In a fourth embodiment, the invention provides a compound represented byFormula (D):

or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate,polymorph, tautomer, stereoisomer, an isotopic form, or a prodrug ofsaid compound of Formula (D) or N-oxide thereof, wherein R₅independently, is nitro, halo, or —SO₂R_(a), wherein R_(a) of R₅ is—(C₁-C₄)alkyl or —(C₁-C₄)haloalkyl;

Z₁ is absent, NH, N(H)(CH₂)_(q), O, S, or —(C₁-C₄)alkylene, wherein q is1, 2, or 3;

L is absent or —(C₁-C₄)alkylene optionally substituted with—(C₃-C₆)cycloalkyl; and

R₆ is H, D, —N(CH₃)—(C₁-C₄)alkylene-P(O)((C₁-C₄)alkoxy)₂,—P(O)(N(CH₃)₂)(OEt), —P(O)(O—(C₁-C₄)alkylene-O—CO—(C₁-C₄)alkyl)₂,—(C₃-C₆)cycloalkyl, phenyl, 5-7 membered heterocyclyl, 8-10 memberedbicyclic ring, wherein the —(C₃-C₆)cycloalkyl, phenyl, 5-7 memberedheterocyclyl, or 7-10 membered bicyclic ring is optionally substitutedwith halo, —OH, —CN, —COOH, —NH₂, —N(CH₃)₂, —(C₁-C₄)alkyl,—(C₁-C₄)alkoxy, cyclopropyl, 4-6 membered heterocyclyl, —CH₂P(O)(OH)₂,—CH₂P(O)((C₁-C₄)alkoxy)₂, —P(O)((C₁-C₄)alkyl)₂, or—N═S(O)((C₁-C₄)alkyl)₂, and the remaining variables are as defined inthe first, second, and/or third embodiments.

In a fifth embodiment, the invention provides a compound according toStructural Formula A, B, C, or D, or an N-oxide thereof, or apharmaceutically acceptable salt, solvate, polymorph, tautomer,stereoisomer, an isotopic form, or a prodrug of said compound of FormulaA, B, C, or D, or N-oxide thereof, wherein R₉ independently, is D, halo,—OH, CN, —NH₂, ═O, —(C₁-C₄)alkyl, —(C₁-C₄)alkoxy, —(C₁-C₄)haloalkyl,—(C₁-C₄)hydroxyalkyl, —(C₃-C₆)cycloalkyl, or 1,3-dithiolanyl; and k is0, 1, 2, 3, or 4; and the remaining variables are as defined in thefirst, second, third, and/or fourth embodiments.

In a sixth embodiment, the invention provides a compound according toStructural Formula A, B, C, or D, or an N-oxide thereof, or apharmaceutically acceptable salt, solvate, polymorph, tautomer,stereoisomer, an isotopic form, or a prodrug of said compound of FormulaA, B, C, or D, or N-oxide thereof, wherein A is —CH₂— or —O—; and theremaining variables are as defined in the first, second, third, fourth,and/or fifth embodiments.

In a seventh embodiment, the invention provides a compound according toStructural Formula A, B, C, or D, or an N-oxide thereof, or apharmaceutically acceptable salt, solvate, polymorph, tautomer,stereoisomer, an isotopic form, or a prodrug of said compound of FormulaA, B, C, or D or N-oxide thereof, wherein each R₂ independently is —CH₃;and n is 0 or 2; and the remaining variables are as defined in thefirst, second, third, fourth, fifth and/or sixth embodiments.

In an eighth embodiment, the invention provides a compound according toStructural Formula A, B, C, or D, or an N-oxide thereof, or apharmaceutically acceptable salt, solvate, polymorph, tautomer,stereoisomer, an isotopic form, or a prodrug of said compound of FormulaA, B, C, or D, or N-oxide thereof, wherein Z₂ is —O—; and the remainingvariables are as defined in the first, second, third, fourth, fifth,sixth and/or seventh embodiments.

In a ninth embodiment, the invention provides a compound according toStructural Formula A, B, C, or D, or an N-oxide thereof, or apharmaceutically acceptable salt, solvate, polymorph, tautomer,stereoisomer, an isotopic form, or a prodrug of said compound of FormulaA, B, C, or D, or N-oxide thereof, wherein R₁ is halo, such as Cl; andthe remaining variables are as defined in the first, second, third,fourth, fifth, sixth, seventh, and/or eighth embodiments.

In a tenth embodiment, the invention provides a compound according toStructural Formula A, B, C, or D, or an N-oxide thereof, or apharmaceutically acceptable salt, solvate, polymorph, tautomer,stereoisomer, an isotopic form, or a prodrug of said compound of FormulaA, B, C, or D or N-oxide thereof, wherein R₅ is nitro; and the remainingvariables are as defined in the first, second, third, fourth, fifth,sixth, seventh, eighth, and/or ninth embodiments.

In an eleventh embodiment, the invention provides a compound accordingto Structural Formula A, B, C, or D, or an N-oxide thereof, or apharmaceutically acceptable salt, solvate, polymorph, tautomer,stereoisomer, an isotopic form, or a prodrug of said compound of FormulaA, B, C, or D or N-oxide thereof, wherein Z₁ is absent, NH or O; and theremaining variables are as defined in the first, second, third, fourth,fifth, sixth, seventh, eighth, ninth, and/or tenth embodiments.

In a twelfth embodiment, the invention provides a compound according toStructural Formula A, B, C, or D, or an N-oxide thereof, or apharmaceutically acceptable salt, solvate, polymorph, tautomer,stereoisomer, an isotopic form, or a prodrug of said compound of FormulaA, B, C, or D or N-oxide thereof, wherein Z₂ is —O—, —CH₂—, —C(O)—,—NH—, —N-(oxetanyl)-, —S—, —S(O)—, —S(O₂)—, —S(O)(═NH)—, —S(O)(═NCH₃)—,or —P(O)(CH₃)—; and the remaining variables are as defined in the first,second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth,and/or eleventh embodiments.

In a thirteenth embodiment, the invention provides a compound accordingto Structural Formula A, B, C, or D, or an N-oxide thereof, or apharmaceutically acceptable salt, solvate, polymorph, tautomer,stereoisomer, an isotopic form, or a prodrug of said compound of FormulaA, B, C, or D or N-oxide thereof, wherein R₆ is H, D,—(C₃-C₆)cycloalkyl, phenyl, tetrahydro-2H-pyranyl, or 1,4-dioxanyl,wherein the —(C₃-C₆)cycloalkyl, phenyl, tetrahydro-2H-pyranyl or1,4-dioxanyl is optionally substituted with 1 or 2 groups selected fromhalogen, —OH, ═O, —(C₁-C₄)alkyl, or —(C₁-C₄)alkoxy; and the remainingvariables are as defined in the first, second, third, fourth, fifth,sixth, seventh, eighth, ninth, tenth, eleventh, and/or twelfthembodiments.

In a fourteenth embodiment, the invention provides a compound accordingto Structural Formula A, B, C, or D, or an N-oxide thereof, or apharmaceutically acceptable salt, solvate, polymorph, tautomer,stereoisomer, an isotopic form, or a prodrug of said compound of FormulaA, B, C, or D or N-oxide thereof, wherein R₆ is tetrahydro-2H-pyranyl or1,4-dioxanyl, wherein the tetrahydro-2H-pyranyl or 1,4-dioxanyl isoptionally substituted with 1 or 2 halogen; and the remaining variablesare as defined in the first, second, third, fourth, fifth, sixth,seventh, eighth, ninth, tenth, eleventh, twelfth, and/or thirteenthembodiments.

For example, in a compound according to Structural Formula A, B, C, orD, or an N-oxide thereof, or a pharmaceutically acceptable salt,solvate, polymorph, tautomer, stereoisomer, an isotopic form, or aprodrug of said compound of Formula A, B, C, or D or N-oxide thereof, Z₁is —NH—, L is —CH₂—, R₆ is tetrahydro-2H-pyranyl or 1,4-dioxanyloptionally substituted with 1 or 2 groups of halogen, and, preferably Ais —CH₂— or —O—, R₁ is Cl, R₅ is nitro, Z₂ is —O—, each R₂ independentlyis —CH₃ and n is 0 or 2, and R₉ is methyl (and k is 1) or halo (and k is2, such as di-fluoro).

A modified compound of any one of such compounds including amodification having an improved (e.g., enhanced, greater) pharmaceuticalsolubility, stability, bioavailability, and/or therapeutic index ascompared to the unmodified compound is also contemplated. Exemplarymodifications include (but are not limited to) applicable prodrugderivatives, and deuterium-enriched compounds.

Also within the scope of this invention is a pharmaceutical compositioncontaining one or more of the compounds (such as any one of those inFormulae (A)-(D), or a pharmaceutically acceptable salt, solvate,polymorph, tautomer, stereoisomer, an isotopic form, or a prodrugthereof or an N-oxide thereof), modifications, and/or salts thereofdescribed herein, and a pharmaceutically acceptable diluent or carrier,for use in treating a neoplastic disease, therapeutic uses thereof, anduse of the compounds for the manufacture of a medicament for treatingthe disease/disorder.

This invention also relates to a method of treating a neoplastic diseaseor an autoimmune disease by administering to a subject in need thereofan effective amount of one or more compounds of the invention (such asany one of those in Formulae (A)-(D), or a pharmaceutically acceptablesalt, solvate, polymorph, tautomer, stereoisomer, an isotopic form, or aprodrug thereof or an N-oxide thereof), modifications, and/or saltsthereof described herein, or a pharmaceutical composition comprising thecompound(s) of the invention.

In certain embodiments, the neoplastic disease, autoimmune disease, orneorodegenerative disease is characterized by abnormal (e.g., enhancedor increased) Bcl-2 activity. For example, the neoplastic disease can bea hematological malignancy or cancer including solid tumor; theautoimmune disease can be type I diabetes; and the neorodegenerativedisease can be schizophrenia.

In certain embodiments, the neoplastic disease is myeloma, multiplemyeloma, lymphoma, follicular lymphoma (FL), non-Hodgkin's lymphoma,leukemia, acute leukemia, acute lymphoblastic leukemia (ALL) (such asBCL-2-dependent ALL and pediatric ALL), chronic lymphoblastic leukemia(CLL) (such as relapsed/refractory CLL, del(17p) CLL), chronic myeloidleukemia (CML) (such as blast-crisis CML), mantle cell lymphoma (MCL),diffuse large B-cell lymphoma, lung cancer such as small cell lungcancer (SCLC), melanoma, breast cancer, or prostate cancer, includingdrug-resistant cancer thereof.

In certain embodiments, the method further comprises administering oneor more further treatment(s) effective to treat the neoplastic disease,such as surgery, radiation therapy, a chemotherapeutic agent (such asbendamustine, NL-101(7-(5-(bis(2-chloroethyl)amino)-1-methyl-1H-benzo[d]imidazol-2-yl)-N-hydroxyheptanamide),cisplatin, carboplatin, etoposide, topotecan), a target therapy (e.g.,an anti-CD20 antibody such as rituximab, a Bruton's tyrosine kinaseinhibitor such as ibrutinib and acalabrutinib (ACP-196), a PI3Kδinhibitor such as idelalisib); an antibody-drug conjugate or ADC (suchas anti-CD30 ADC brentuximab vedotin), an immunotherapy (such as ananti-PD-1 antibody including pembrolizumab and nivolumab, or ananti-PD-L1 antibody including atezolizumab, durvalumab, and avelumab),or a CAR-T therapy (such as tisagenlecleucel, axicabtagene ciloleucel).

Also provided herein is the use of one or more compounds of theinvention, or a pharmaceutically acceptable salt thereof, or apharmaceutical composition comprising one or more compounds of theinvention, for the preparation of a medicament for the treatment of theabove-referenced diseases or conditions.

In another embodiment, provided herein the compounds of the invention,or a pharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition comprising one or more of the disclosed compounds are foruse in treating the above-referenced diseases or conditions.

The details of one or more embodiments of the invention are set forth inthe description below. Other features, objects, and advantages of theinvention will be apparent from the description and from the claims. Itshould be understood that all embodiments/features of the invention(compounds, pharmaceutical compositions, methods of make/use, etc)described herein, including any specific features described in theexamples and original claims, can combine with one another unless notapplicable or explicitly disclaimed.

DETAILED DESCRIPTION OF THE INVENTION

Exemplary compounds described herein include, but are not limited to,the following:

-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl-2,2,3,3-d4)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3-methyl-2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,3-dimethyl-2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   (R)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2-methyl-2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   (S)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3-methyl-2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]thiazin-1(6H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   (R)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2-(3-(trifluoromethyl)-2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)benzamide,-   (R)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2-(3-(trifluoromethyl)-2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]thiazin-1(6H)-yl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-(2-methyl-2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)benzamide,-   (S)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-(3-methyl-2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,2-dimethyl-2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-(2′H-spiro[cyclopropane-1,3′-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin]-1′(6′H)-yl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-(2,3,4,6-tetrahydro-1H-pyrrolo[2,3-b][1,5]naphthyridin-1-yl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-(2-oxo-2,3,4,6-tetrahydro-1H-pyrrolo[2,3-b][1,5]naphthyridin-1-yl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-(3-oxo-2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-(4-oxo-2,3,4,6-tetrahydro-1H-pyrrolo[2,3-b][1,5]naphthyridin-1-yl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-(2,3,4,6-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[2,3-b]pyrazin-1-yl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(4,4-dioxido-2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]thiazin-1(6H)-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-(4-(methylimino)-4-oxido-2,3,4,6-tetrahydro-1H-4M-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]thiazin-1-yl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-3-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((4-((2-morpholinoethyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   (R)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((4-(((4-methylmorpholin-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   (R)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((3-nitro-4-(((4-(oxetan-3-yl)morpholin-2-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((4-(((4-hydroxycyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((4-((((1r,4r)-4-methoxycyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((4-((((1s,4s)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((4-((((1s,4s)-4-ethyl-4-hydroxycyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((3-nitro-4-((1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)amino)phenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((4-(((1s,4s)-4-morpholinocyclohexyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((4-(cyclopropylamino)cyclohexyl)amino)-3-nitrophenyl)sulfonyl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-(((4,4-difluorocyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-3-yl)methoxy)phenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((4-(2-morpholinoethoxy)-3-nitrophenyl)sulfonyl)benzamide,-   (S)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((4-((4-methylmorpholin-2-yl)methoxy)-3-nitrophenyl)sulfonyl)benzamide,-   (S)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((3-nitro-4-((4-(oxetan-3-yl)morpholin-2-yl)methoxy)phenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((4-((4-hydroxycyclohexyl)methoxy)-3-nitrophenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((4-(((1r,4r)-4-methoxycyclohexyl)methoxy)-3-nitrophenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((4-(((1s,4s)-4-hydroxy-4-methylcyclohexyl)methoxy)-3-nitrophenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((4-(((1s,4s)-4-ethyl-4-hydroxycyclohexyl)methoxy)-3-nitrophenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((3-nitro-4-((1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)oxy)phenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((4-(((1s,4s)-4-morpholinocyclohexyl)oxy)-3-nitrophenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((4-(cyclopropylamino)cyclohexyl)oxy)-3-nitrophenyl)sulfonyl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((4,4-difluorocyclohexyl)methoxy)-3-nitrophenyl)sulfonyl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)benzamide,-   4-(4-((2-(4-chlorophenyl)cyclopent-1-en-1-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   4-(4-((2-(4-chlorophenyl)cyclohept-1-en-1-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   4-(4-((4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-4-(methoxymethyl)-4-methyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-5-fluoro-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((6-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-5-nitropyridin-3-yl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(6,7-dihydroimidazo[4′,5′:5,6]pyrido[2,3-b][1,4]oxazin-8(3H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   4-(4-((9-(4-chlorophenyl)-3-methyl-3-azaspiro[5.5]undec-8-en-8-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   4-(4-((9-(4-chlorophenyl)-3-(1,3-difluoropropan-2-yl)-3-azaspiro[5.5]undec-8-en-8-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-difluoro-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   4-(4-((5-(4-chlorophenyl)spiro[2.5]oct-5-en-6-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   4-(4-((7-(4-chlorophenyl)spiro[3.5]non-6-en-6-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-3′-fluoro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-3′,5,5-trimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-4-(4-((4,4-dimethyl-2-(pyridin-3-yl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   4-(4-((2-(1H-indol-5-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   (R)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-fluoro-5-nitrophenyl)sulfonyl)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)benzamide,-   (R)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)benzamide,-   (R)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((6-(4-chlorophenyl)-2-oxaspiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)benzamide,-   (R)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-fluoro-5-nitrophenyl)sulfonyl)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)benzamide,-   4-(4-((6-(4-chlorophenyl)-2-oxaspiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   4-(4-((6-(4-chlorophenyl)-2-oxaspiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   (S)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-6-fluorobenzamide,-   (S)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-5-fluorobenzamide,-   4-(4-((4′-chloro-5,5-bis(methyl-d3)-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)-2-methylpiperazin-1-yl-2,3,3,5,5,6,6-d7)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   diethyl    ((2-(((4-(N-(4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)benzoyl)sulfamoyl)-2-nitrophenyl)amino)methyl)morpholino)methyl)phosphonate,-   diethyl    (((3-((4-(N-(4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)benzoyl)sulfamoyl)-2-nitrophenyl)amino)propyl)(methyl)amino)methyl)phosphonate,-   2-(((2-((4-(N-(4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)benzoyl)sulfamoyl)-2-nitrophenyl)amino)ethyl)((pivaloyloxy)methoxy)phosphoryl)oxy)ethyl    pivalate,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((4-(((1-methyl-1-oxidophosphinan-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((4-(((1-hydroxy-1-oxidophosphinan-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   ((4-(((4-(N-(4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)benzoyl)sulfamoyl)-2-nitrophenyl)amino)methyl)-1-oxidophosphinan-1-yl)oxy)methyl    pivalate,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((4-(((2-methyl-2-oxido-1,3,2-oxazaphosphinan-5-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((4-((2-(2-methyl-2-oxido-1,3,2-oxazaphosphinan-3-yl)ethyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((4-(((1-(dimethylphosphoryl)piperidin-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((3-(dimethylphosphoryl)-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   N-((4-(((1,4-dioxaspiro[4.5]decan-8-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)benzamide,-   N-((4-(((2-oxaspiro[3.5]nonan-7-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((4-((2-(hexahydrofuro[3,4-c]pyridin-5(3H)-yl)ethyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   (R)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((3-nitro-4-((2-(3-oxooctahydro-7H-imidazo[1,5-d][1,4]diazepin-7-yl)ethyl)amino)phenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((3-nitro-4-((2-(3-oxooctahydro-5H-pyrrolo[3,4-c]pyridin-5-yl)ethyl)amino)phenyl)sulfonyl)benzamide,-   N-((4-((2-(2-oxa-5-azabicyclo[2.2.2]octan-5-yl)ethyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((4-(((3-hydroxy-3-methylbicyclo[3.1.1]heptan-6-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   N-((4-((2-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)ethyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)benzamide,-   2-((3R)-8-(2-((4-(N-(4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)benzoyl)sulfamoyl)-2-nitrophenyl)amino)ethyl)-6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl)acetic    acid,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((2-(6,6-difluoro-8-azabicyclo[3.2.1]octan-8-yl)ethyl)amino)-3-nitrophenyl)sulfonyl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((3-nitro-4-((2-(tetrahydro-2H-pyran-4-yl)-2-azaspiro[3.3]heptan-6-yl)amino)phenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-thiopyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((4-(((1-imino-1-oxidohexahydro-1l6-thiopyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((4-(((4-(methylsulfonyl)morpholin-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   N-((4-(((4-aminotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((3-nitro-4-((1-(tetrahydro-2H-pyran-4-yl)cyclopropyl)amino)phenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((2-(5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)ethyl)amino)-3-nitrophenyl)sulfonyl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((3-nitro-4-(((5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-6-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((3-(difluoromethoxy)benzyl)amino)-3-nitrophenyl)sulfonyl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((3-nitro-4-(((3,4,5-trihydroxytetrahydrofuran-2-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((3-nitro-4-(((3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((4-(((4,5-dihydroxy-6,6-dimethyltetrahydro-2H-pyran-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((3-nitro-4-(((2,3,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((3-nitro-4-(((2,3,4,5,6-pentahydroxycyclohexyl)methyl)amino)phenyl)sulfonyl)benzamide-   (R)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(1-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)benzamide,-   4-(1-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   (R)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(1-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperidin-4-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)benzamide,-   (S)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-5-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)-3-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)picolinamide,-   (S)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-6-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)nicotinamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2-methyl-2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,2-dimethyl-2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3-(hydroxymethyl)-2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   (S)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2-methyl-2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   (R)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3-methyl-2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(4,4-dioxido-2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]thiazin-1(6H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   (S)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2-(3-(trifluoromethyl)-2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)benzamide,-   (S)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2-(3-(trifluoromethyl)-2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]thiazin-1(6H)-yl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl-2,2,3,3-d4)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-(3-methyl-2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)benzamide,-   (R)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-(3-methyl-2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,3-dimethyl-2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-(3′H-spiro[cyclopropane-1,2′-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin]-1′(6′H)-yl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]thiazin-1(6H)-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-(2-oxo-2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-(3-oxo-2,3,4,6-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[2,3-b]pyrazin-1-yl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-(4-oxo-4,6-dihydro-1H-pyrrolo[2,3-b][1,5]naphthyridin-1-yl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-(4-methyl-2,3,4,6-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[2,3-b]pyrazin-1-yl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-(4-imino-4-oxido-2,3,4,6-tetrahydro-1H-4M-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]thiazin-1-yl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-(4-methyl-4-oxido-2,3,6-trihydropyrrolo[3′,2′:5,6]pyrido[3,2-b][1,4]azaphosphinin-1-yl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((4-(((3-fluorotetrahydro-2H-pyran-3-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((4-((3-morpholinopropyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   (S)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((4-(((4-methylmorpholin-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   (S)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((3-nitro-4-(((4-(oxetan-3-yl)morpholin-2-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((4-(((4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((4-((((1s,4s)-4-methoxycyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((4-((((1r,4r)-4-ethyl-4-hydroxycyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((3-nitro-4-((1-(oxetan-3-yl)piperidin-4-yl)amino)phenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((4-(((1r,4r)-4-morpholinocyclohexyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((4-((4-(methyl(oxetan-3-yl)amino)cyclohexyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((3-nitro-4-(((1,4,4-trifluorocyclohexyl)methyl)amino)phenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((4-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)-3-nitrophenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((4-((3-fluorotetrahydro-2H-pyran-3-yl)methoxy)-3-nitrophenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((4-(3-morpholinopropoxy)-3-nitrophenyl)sulfonyl)benzamide,-   (R)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((4-((4-methylmorpholin-2-yl)methoxy)-3-nitrophenyl)sulfonyl)benzamide,-   (R)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((3-nitro-4-((4-(oxetan-3-yl)morpholin-2-yl)methoxy)phenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((4-((4-hydroxy-4-methylcyclohexyl)methoxy)-3-nitrophenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((4-(((1s,4s)-4-methoxycyclohexyl)methoxy)-3-nitrophenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((4-(((1r,4r)-4-hydroxy-4-methylcyclohexyl)methoxy)-3-nitrophenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((4-(((1r,4r)-4-ethyl-4-hydroxycyclohexyl)methoxy)-3-nitrophenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((3-nitro-4-((1-(oxetan-3-yl)piperidin-4-yl)oxy)phenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((4-(((1r,4r)-4-morpholinocyclohexyl)oxy)-3-nitrophenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((4-((4-(methyl(oxetan-3-yl)amino)cyclohexyl)oxy)-3-nitrophenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((3-nitro-4-((1,4,4-trifluorocyclohexyl)methoxy)phenyl)sulfonyl)benzamide,-   4-(4-((4-(4-chlorophenyl)-5,6-dihydro-2H-pyran-3-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   (Z)-4-(4-((2-(4-chlorophenyl)cyclooct-1-en-1-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-4-methoxy-4-methyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   4-(5-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)-2,5-diazabicyclo[2.2.2]octan-2-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-(4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenylsulfonimidoyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((5-chloro-6-((tetrahydro-2H-pyran-4-yl)methoxy)pyridin-3-yl)sulfonyl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-(S-(trifluoromethyl)sulfonimidoyl)phenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydro-[1,4]oxazino[3,2-f]indol-1(6H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   4-(4-((9-(4-chlorophenyl)-3-isopropyl-3-azaspiro[5.5]undec-8-en-8-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   4-(4-((9-(4-chlorophenyl)-3-(oxetan-3-yl)-3-azaspiro[5.5]undec-8-en-8-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-bis(fluoromethyl)-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   4-(4-(1-(4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)cyclopropyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   4-(4-((6-(4-chlorophenyl)spiro[2.5]oct-5-en-5-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-2′-fluoro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-2′,5,5-trimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-4-(4-((4,4-dimethyl-2-(pyridin-2-yl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-4-(4-((4,4-dimethyl-2-(1H-pyrrolo[2,3-b]pyridin-5-yl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   (S)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-fluoro-5-nitrophenyl)sulfonyl)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)benzamide,-   (S)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)benzamide,-   (S)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((6-(4-chlorophenyl)-2-oxaspiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)benzamide,-   (S)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-fluoro-5-nitrophenyl)sulfonyl)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)benzamide,-   4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   (S)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-3-fluorobenzamide,-   (S)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-fluoro-5-nitrophenyl)sulfonyl)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-6-fluorobenzamide,-   4-(4-((4′-chloro-5,5-bis(methyl-d3)-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl-2,2,3,3-d4)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   ((2-(((4-(N-(4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)benzoyl)sulfamoyl)-2-nitrophenyl)amino)methyl)morpholino)methyl)phosphonic    acid,-   diethyl    (2-((2-((4-(N-(4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)benzoyl)sulfamoyl)-2-nitrophenyl)amino)ethyl)(methyl)amino)ethyl)phosphonate,-   ethyl    P-(2-((4-(N-(4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)benzoyl)sulfamoyl)-2-nitrophenyl)amino)ethyl)-N,N-dimethylphosphonamidate,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((4-(((1-(dimethylamino)-1-oxidophosphinan-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((4-(((1-ethoxy-1-oxidophosphinan-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((4-(((1-isopropoxy-1-oxidophosphinan-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((3-nitro-4-(((1,2,3-trimethyl-2-oxido-1,3,2-diazaphosphinan-5-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((4-((2-(2-methyl-2-oxido-1,3,2-diazaphosphinan-1-yl)ethyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((4-(((4-(dimethylphosphoryl)morpholin-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((4-(dimethylphosphoryl)-3-nitrophenyl)sulfonyl)benzamide,-   N-((4-(((1,4-dithiaspiro[4.5]decan-8-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)benzamide,-   N-((4-((2-(6-azaspiro[2.5]octan-6-yl)ethyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((2-(2,2-difluoro-7-azaspiro[3.5]nonan-7-yl)ethyl)amino)-3-nitrophenyl)sulfonyl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((3-nitro-4-((2-(2-(oxetan-3-yl)octahydro-5H-pyrrolo[3,4-c]pyridin-5-yl)ethyl)amino)phenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((3-nitro-4-((2-(1-oxooctahydro-5H-pyrrolo[3,4-c]pyridin-5-yl)ethyl)amino)phenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((4-(((3-hydroxybicyclo[3.1.1]heptan-6-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   N-((4-(((3-amino-3-methylbicyclo[3.1.1]heptan-6-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((3-nitro-4-((2-(5-(oxetan-3-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)ethyl)amino)phenyl)sulfonyl)benzamide,-   2-((3S)-8-(2-((4-(N-(4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)benzoyl)sulfamoyl)-2-nitrophenyl)amino)ethyl)-6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl)acetic    acid,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((2-(6,6-difluoro-8-azabicyclo[3.2.1]octan-8-yl)ethyl)amino)-3-nitrophenyl)sulfonyl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)benzamide,-   N-((4-((7-oxaspiro[3.5]nonan-2-yl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((4-(((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((4-(((1-(isopropylimino)-1-oxidohexahydro-1l6-thiopyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((4-(((4-(S-methylsulfonimidoyl)morpholin-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-(((4-cyanotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((3-nitro-4-((2-(tetrahydro-2H-pyran-4-yl)propan-2-yl)amino)phenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((2-(5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl)ethyl)amino)-3-nitrophenyl)sulfonyl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((3-nitro-4-(((1-(thiazol-2-yl)piperidin-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((4-(difluoromethoxy)benzyl)amino)-3-nitrophenyl)sulfonyl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((4-(((3,5-dihydroxytetrahydrofuran-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((3-nitro-4-(((3,4,5-trihydroxy-6,6-dimethyltetrahydro-2H-pyran-2-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((3-nitro-4-(((2,3,5-trihydroxytetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((3-nitro-4-(((3,4,5-trihydroxy-6-(methylthio)tetrahydro-2H-pyran-2-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((3-nitro-4-(((3,4,5-trihydroxy-6-(((4,5,6-trihydroxy-2-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)methoxy)methyl)tetrahydro-2H-pyran-2-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(1-((6-(4-chlorophenyl)-2-oxaspiro[3.5]non-6-en-7-yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)benzamide,-   4-(1-((6-(4-chlorophenyl)-2-oxaspiro[3.5]non-6-en-7-yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   (R)-4-(1-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperidin-4-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-3-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   (S)-6-(4-((6-(4-chlorophenyl)-2-oxaspiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)-4-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-3-yl)methyl)amino)phenyl)sulfonyl)nicotinamide,-   (S)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-6-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)nicotinamide,-   N-((4-((((R)-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-((S)-3-methyl-2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((((S)-2-fluoro-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((S)-3-methyl-2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)benzamide,-   (R)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)benzamide,-   (S)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((4-(((2-fluoro-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   (R)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,3-difluoro-2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)benzamide,-   (S)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,3-difluoro-2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((4-(((2-fluoro-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,3-difluoro-2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   N-((4-((((S)-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-((S)-3-methyl-2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((((R)-2-fluoro-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((S)-3-methyl-2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)benzamide,-   (S)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)benzamide,-   (R)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((4-(((2-fluoro-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   (S)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,3-difluoro-2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)benzamide,-   (R)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,3-difluoro-2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((4-(((2-fluoro-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,3-difluoro-2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((4-(((4-((dimethyl(oxo)-16-sulfaneylidene)amino)cyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((4-((2-(4-((dimethyl(oxo)-16-sulfaneylidene)amino)piperidin-1-yl)ethyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((3-nitro-4-(((4-((1-oxidotetrahydro-1l6-thiophen-1-ylidene)amino)cyclohexyl)methyl)amino)phenyl)sulfonyl)benzamide,    or-   (S)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((4-((1-(4-((dimethyl(oxo)-16-sulfaneylidene)amino)piperidin-1-yl)propan-2-yl)amino)-3-nitrophenyl)sulfonyl)benzamide.

Compounds of the invention may contain one or more asymmetric carbonatoms. Accordingly, the compounds may exist as diastereomers,enantiomers or mixtures thereof. The syntheses of the compounds mayemploy racemates, diastereomers or enantiomers as starting materials oras intermediates. Diastereomeric compounds may be separated bychromatographic or crystallization methods. Similarly, enantiomericmixtures may be separated using the same techniques or others known inthe art. Each of the asymmetric carbon atoms may be in the R or Sconfiguration, and both of these configurations are within the scope ofthe invention.

Compounds having one or more chiral centers can exist in variousstereoisomeric forms. Stereoisomers are compounds that differ only intheir spatial arrangement. Stereoisomers include all diastereomeric,enantiomeric, and epimeric forms as well as racemates and mixturesthereof.

The term “geometric isomer” refers to cyclic compounds having at leasttwo substituents, wherein the two substituents are both on the same sideof the ring (cis) or wherein the substituents are each on opposite sidesof the ring (trans). When a disclosed compound is named or depicted bystructure without indicating stereochemistry, it is understood that thename or the structure encompasses one or more of the possiblestereoisomers, or geometric isomers, or a mixture of the encompassedstereoisomers or geometric isomers.

When a geometric isomer is depicted by name or structure, it is to beunderstood that the named or depicted isomer exists to a greater degreethan another isomer, that is that the geometric isomeric purity of thenamed or depicted geometric isomer is greater than 50%, such as at least60%, 70%, 80%, 90%, 99%, or 99.9% pure by weight. Geometric isomericpurity is determined by dividing the weight of the named or depictedgeometric isomer in the mixture by the total weight of all of thegeomeric isomers in the mixture.

Racemic mixture means 50% of one enantiomer and 50% of is correspondingenantiomer. When a compound with one chiral center is named or depictedwithout indicating the stereochemistry of the chiral center, it isunderstood that the name or structure encompasses both possibleenantiomeric forms (e.g., both enantiomerically-pure,enantiomerically-enriched or racemic) of the compound. When a compoundwith two or more chiral centers is named or depicted without indicatingthe stereochemistry of the chiral centers, it is understood that thename or structure encompasses all possible diasteriomeric forms (e.g.,diastereomerically pure, diastereomerically enriched and equimolarmixtures of one or more diastereomers (e.g., racemic mixtures) of thecompound.

Enantiomeric and diastereomeric mixtures can be resolved into theircomponent enantiomers or stereoisomers by well-known methods, such aschiral-phase gas chromatography, chiral-phase high performance liquidchromatography, crystallizing the compound as a chiral salt complex, orcrystallizing the compound in a chiral solvent.

Enantiomers and diastereomers also can be obtained fromdiastereomerically- or enantiomerically-pure intermediates, reagents,and catalysts by well-known asymmetric synthetic methods.

When a compound is designated by a name or structure that indicates asingle enantiomer, unless indicated otherwise, the compound is at least60%, 70%, 80%, 90%, 99% or 99.9% optically pure (also referred to as“enantiomerically pure”). Optical purity is the weight in the mixture ofthe named or depicted enantiomer divided by the total weight in themixture of both enantiomers.

When the stereochemistry of a disclosed compound is named or depicted bystructure, and the named or depicted structure encompasses more than onestereoisomer (e.g., as in a diastereomeric pair), it is to be understoodthat one of the encompassed stereoisomers or any mixture of theencompassed stereoisomers is included. It is to be further understoodthat the stereoisomeric purity of the named or depicted stereoisomers atleast 60%, 70%, 80%, 90%, 99% or 99.9% by weight. The stereoisomericpurity in this case is determined by dividing the total weight in themixture of the stereoisomers encompassed by the name or structure by thetotal weight in the mixture of all of the stereoisomers.

A modified compound of any one of such compounds including amodification having an improved (e.g., enhanced, greater) pharmaceuticalsolubility, stability, bioavailability and/or therapeutic index ascompared to the unmodified compound is also contemplated. The examplesof modifications include but not limited to the prodrug derivatives, andthe deuterium-enriched compounds. For example:

-   -   Prodrug derivatives: prodrugs, upon administration to a subject,        will converted in vivo into active compounds of the present        invention [Nature Reviews of Drug Discovery, 2008, Volume 7,        p255]. It is noted that in many instances, the prodrugs        themselves also fall within the scope of the range of compounds        according to the present invention.    -   The prodrugs of the compounds of the present invention can be        prepared by standard organic reaction, for example, by reacting        with a carbamylating agent (e.g.,        1,1-acyloxyalkylcarbonochloridate, para-nitrophenyl carbonate,        or the like) or an acylating agent. Further examples of methods        and strategies of making prodrugs are described in Bioorganic        and Medicinal Chemistry Letters, 1994, Vol. 4, p. 1985.    -   Deuterium-enriched compounds: deuterium (D or ²H) is a stable,        non-radioactive isotope of hydrogen and has an atomic weight of        2.0144. Hydrogen naturally occurs as a mixture of the isotopes        ^(X)H (hydrogen or protium), D (²H or deuterium), and T (³H or        tritium). The natural abundance of deuterium is 0.015%. One of        ordinary skill in the art recognizes that in all chemical        compounds with a H atom, the H atom actually represents a        mixture of H and D, with about 0.015% being D. Thus, compounds        with a level of deuterium that has been enriched to be greater        than its natural abundance of 0.015%, should be considered        unnatural and, as a result, novel over their nonenriched        counterparts.

It should be recognized that the compounds of the present invention maybe present and optionally administered in the form of salts, andsolvates. The invention encompasses any pharmaceutically acceptablesalts and solvates of any one of the above-described compounds andmodifications thereof. For example, it is within the scope of thepresent invention to convert the compounds of the present invention intoand use them in the form of their pharmaceutically acceptable saltsderived from various organic and inorganic acids and bases in accordancewith procedures well known in the art.

When the compounds of the present invention possess a free base form,the compounds can be prepared as a pharmaceutically acceptable acidaddition salt by reacting the free base form of the compound with apharmaceutically acceptable inorganic or organic acid, e.g.,hydrohalides such as hydrochloride, hydrobromide, hydroiodide; othermineral acids such as sulfate, nitrate, phosphate, etc.; and alkyl andmonoarylsulfonates such as ethanesulfonate, toluenesulfonate andbenzenesulfonate; and other organic acids and their corresponding saltssuch as acetate, tartrate, maleate, succinate, citrate, benzoate,salicylate and ascorbate. Further acid addition salts of the presentinvention include, but are not limited to: adipate, alginate, arginate,aspartate, bisulfate, bisulfite, bromide, butyrate, camphorate,camphorsulfonate, caprylate, chloride, chlorobenzoate,cyclopentanepropionate, digluconate, dihydrogenphosphate,dinitrobenzoate, dodecylsulfate, fumarate, galacterate (from mucicacid), galacturonate, glucoheptaoate, gluconate, glutamate,glycerophosphate, hemisuccinate, hemisulfate, heptanoate, hexanoate,hippurate, 2-hydroxyethanesulfonate, iodide, isethionate, iso-butyrate,lactate, lactobionate, malonate, mandelate, metaphosphate,methanesulfonate, methylbenzoate, monohydrogenphosphate,2-naphthalenesulfonate, nicotinate, oxalate, oleate, pamoate, pectinate,persulfate, phenylacetate, 3-phenylpropionate, phosphonate andphthalate. It should be recognized that the free base forms willtypically differ from their respective salt forms somewhat in physicalproperties such as solubility in polar solvents, but otherwise the saltsare equivalent to their respective free base forms for the purposes ofthe present invention.

When the compounds of the present invention possess a free acid form, apharmaceutically acceptable base addition salt can be prepared byreacting the free acid form of the compound with a pharmaceuticallyacceptable inorganic or organic base. Examples of such bases are alkalimetal hydroxides including potassium, sodium and lithium hydroxides;alkaline earth metal hydroxides such as barium and calcium hydroxides;alkali metal alkoxides, e.g., potassium ethanolate and sodiumpropanolate; and various organic bases such as ammonium hydroxide,piperidine, diethanolamine and N-methylglutamine. Also included are thealuminum salts of the compounds of the present invention. Further basesalts of the present invention include, but are not limited to: copper,ferric, ferrous, lithium, magnesium, manganic, manganous, potassium,sodium and zinc salts. Organic base salts include, but are not limitedto, salts of primary, secondary and tertiary amines, substituted aminesincluding naturally occurring substituted amines, cyclic amines andbasic ion exchange resins, e.g., arginine, betaine, caffeine,chloroprocaine, choline, N,N′-dibenzylethylenediamine (benzathine),dicyclohexylamine, diethanolamine, 2-diethylaminoethanol,2-dimethylaminoethanol, ethanolamine, ethylenediamine,N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine,hydrabamine, iso-propylamine, lidocaine, lysine, meglumine,N-methyl-D-glucamine, morpholine, piperazine, piperidine, polyamineresins, procaine, purines, theobromine, triethanolamine, triethylamine,trimethylamine, tripropylamine and tris-(hydroxymethyl)-methylamine(tromethamine). It should be recognized that the free acid forms willtypically differ from their respective salt forms somewhat in physicalproperties such as solubility in polar solvents, but otherwise the saltsare equivalent to their respective free acid forms for the purposes ofthe present invention.

In one aspect, a pharmaceutically acceptable salt is a hydrochloridesalt, hydrobromide salt, methanesulfonate, toluenesulfonate, acetate,fumarate, sulfate, bisulfate, succinate, citrate, phosphate, maleate,nitrate, tartrate, benzoate, biocarbonate, carbonate, sodium hydroxidesalt, calcium hydroxide salt, potassium hydroxide salt, tromethaminesalt, or mixtures thereof.

Compounds of the present invention that comprise tertiarynitrogen-containing groups may be quaternized with such agents as (C₁₋₄)alkyl halides, e.g., methyl, ethyl, iso-propyl and tert-butyl chlorides,bromides and iodides; di-(C₁₋₄) alkyl sulfates, e.g., dimethyl, diethyland diamyl sulfates; alkyl halides, e.g., decyl, dodecyl, lauryl,myristyl and stearyl chlorides, bromides and iodides; and aryl (C₁₋₄)alkyl halides, e.g., benzyl chloride and phenethyl bromide. Such saltspermit the preparation of both water- and oil-soluble compounds of theinvention.

Amine oxides, also known as amine-N-oxide and N-oxide, of anti-canceragents with tertiary nitrogen atoms have been developed as prodrugs [MolCancer Therapy. 2004 March; 3(3):233-44]. Compounds of the presentinvention that comprise tertiary nitrogen atoms may be oxidized by suchagents as hydrogen peroxide (H₂O₂), Caro's acid or peracids likemeta-Chloroperoxybenzoic acid (mCPBA) to from amine oxide.

The compounds disclosed therein are bcl-2 inhibitors. The pharmaceuticalcomposition of the present invention comprises one or more bcl-2inhibitors, or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable carrier or diluent.

“Pharmaceutically acceptable carrier” and “pharmaceutically acceptablediluent” refer to a substance that aids the formulation and/oradministration of an active agent to and/or absorption by a subject andcan be included in the compositions of the present disclosure withoutcausing a significant adverse toxicological effect on the subject.Non-limiting examples of pharmaceutically acceptable carriers and/ordiluents include water, NaCl, normal saline solutions, lactatedRinger's, normal sucrose, normal glucose, binders, fillers,disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions(such as Ringer's solution), alcohols, oils, gelatins, carbohydratessuch as lactose, amylose or starch, fatty acid esters,hydroxymethycellulose, polyvinyl pyrrolidine, and colors, and the like.Such preparations can be sterilized and, if desired, mixed withauxiliary agents such as lubricants, preservatives, stabilizers, wettingagents, emulsifiers, salts for influencing osmotic pressure, buffers,coloring, and/or aromatic substances and the like that do notdeleteriously react with or interfere with the activity of the compoundsprovided herein. One of ordinary skill in the art will recognize thatother pharmaceutical excipients are suitable for use with disclosedcompounds.

The pharmaceutical compositions of the present invention optionallyinclude one or more pharmaceutically acceptable carriers and/or diluentstherefor, such as lactose, starch, cellulose and dextrose. Otherexcipients, such as flavoring agents; sweeteners; and preservatives,such as methyl, ethyl, propyl and butyl parabens, can also be included.More complete listings of suitable excipients can be found in theHandbook of Pharmaceutical Excipients (5^(th) Ed., Pharmaceutical Press(2005)). A person skilled in the art would know how to prepareformulations suitable for various types of administration routes.Conventional procedures and ingredients for the selection andpreparation of suitable formulations are described, for example, inRemington's Pharmaceutical Sciences (2003—20th edition) and in TheUnited States Pharmacopeia: The National Formulary (USP 24 NF19)published in 1999. The carriers, diluents and/or excipients are“acceptable” in the sense of being compatible with the other ingredientsof the pharmaceutical composition and not deleterious to the recipientthereof.

The pharmaceutical compositions of the present invention may furthercomprise other conventional pharmaceutically inactive agents. Any inertexcipient that is commonly used as a carrier or diluent may be used incompositions of the present invention, such as sugars, polyalcohols,soluble polymers, salts and lipids. Sugars and polyalcohols which may beemployed include, without limitation, lactose, sucrose, mannitol, andsorbitol. Illustrative of the soluble polymers which may be employed arepolyoxyethylene, poloxamers, polyvinylpyrrolidone, and dextran. Usefulsalts include, without limitation, sodium chloride, magnesium chloride,and calcium chloride. Lipids which may be employed include, withoutlimitation, fatty acids, glycerol fatty acid esters, glycolipids, andphospholipids.

In addition, the pharmaceutical compositions of the present inventionmay further comprise binders (e.g., acacia, cornstarch, gelatin,carbomer, ethyl cellulose, guar gum, hydroxypropyl cellulose,hydroxypropyl methyl cellulose, povidone), disintegrating agents (e.g.,cornstarch, potato starch, alginic acid, silicon dioxide, croscarmellosesodium, crospovidone, guar gum, sodium starch glycolate, Primogel),buffers (e.g., tris-HCL, acetate, phosphate) of various pH and ionicstrength, additives such as albumin or gelatin to prevent absorption tosurfaces, detergents (e.g., Tween 20, Tween 80, Pluronic F68, bile acidsalts), protease inhibitors, surfactants (e.g., sodium lauryl sulfate),permeation enhancers, solubilizing agents (e.g., glycerol, polyethyleneglycerol, cyclodextrins), a glidant (e.g., colloidal silicon dioxide),anti-oxidants (e.g., ascorbic acid, sodium metabisulfite, butylatedhydroxyanisole), stabilizers (e.g., hydroxypropyl cellulose,hydroxypropylmethyl cellulose), viscosity increasing agents (e.g.,carbomer, colloidal silicon dioxide, ethyl cellulose, guar gum),sweeteners (e.g., sucrose, aspartame, citric acid), flavoring agents(e.g., peppermint, methyl salicylate, or orange flavoring),preservatives (e.g., Thimerosal, benzyl alcohol, parabens), lubricants(e.g., stearic acid, magnesium stearate, polyethylene glycol, sodiumlauryl sulfate), flow-aids (e.g., colloidal silicon dioxide),plasticizers (e.g., diethyl phthalate, triethyl citrate), emulsifiers(e.g., carbomer, hydroxypropyl cellulose, sodium lauryl sulfate, methylcellulose, hydroxyethyl cellulose, carboxymethylcellulose sodium),polymer coatings (e.g., poloxamers or poloxamines), coating and filmforming agents (e.g., ethyl cellulose, acrylates, polymethacrylates)and/or adjuvants.

In one embodiment, the pharmaceutical compositions are prepared withcarriers that will protect the compound against rapid elimination fromthe body, such as a controlled release formulation, including implantsand microencapsulated delivery systems. Biodegradable, biocompatiblepolymers can be used, such as ethylene vinyl acetate, polyanhydrides,polyglycolic acid, collagen, polyorthoesters, and polylactic acid.Methods for preparation of such formulations will be apparent to thoseskilled in the art. The materials can also be obtained commercially fromAlza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions(including liposomes targeted to infected cells with monoclonalantibodies to viral antigens) can also be used as pharmaceuticallyacceptable carriers. These can be prepared according to methods known tothose skilled in the art, for example, as described in U.S. Pat. No.4,522,811.

Additionally, the invention encompasses pharmaceutical compositionscomprising any solid or liquid physical form of the compound of theinvention. For example, the compounds can be in a crystalline form, inamorphous form, and have any particle size. The particles may bemicronized, or may be agglomerated, particulate granules, powders, oils,oily suspensions or any other form of solid or liquid physical form.

When compounds according to the present invention exhibit insufficientsolubility, methods for solubilizing the compounds may be used. Suchmethods are known to those of skill in this art, and include, but arenot limited to, pH adjustment and salt formation, using co-solvents,such as ethanol, propylene glycol, polyethylene glycol (PEG) 300, PEG400, DMA (10-30%), DMSO (10-20%), NMP (10-20%), using surfactants, suchas polysorbate 80, polysorbate 20 (1-10%), cremophor EL, Cremophor RH40,Cremophor RH60 (5-10%), Pluronic F68/Poloxamer 188 (20-50%), SolutolHS15 (20-50%), Vitamin E TPGS, and d-α-tocopheryl PEG 1000 succinate(20-50%), using complexation such as HPβCD and SBEβCD (10-40%), andusing advanced approaches such as micelle, addition of a polymer,nanoparticle suspensions, and liposome formation.

A wide variety of administration methods may be used in conjunction withthe compounds of the present invention. Compounds of the presentinvention may be administered or coadministered orally, parenterally,intraperitoneally, intravenously, intraarterially, transdermally,sublingually, intramuscularly, rectally, transbuccally, intranasally,liposomally, via inhalation, vaginally, intraoccularly, via localdelivery (for example by catheter or stent), subcutaneously,intraadiposally, intraarticularly, or intrathecally. The compoundsaccording to the invention may also be administered or coadministered inslow release dosage forms. Compounds may be in gaseous, liquid,semi-liquid or solid form, formulated in a manner suitable for the routeof administration to be used. For oral administration, suitable solidoral formulations include tablets, capsules, pills, granules, pellets,sachets and effervescent, powders, and the like. Suitable liquid oralformulations include solutions, suspensions, dispersions, emulsions,oils and the like. For parenteral administration, reconstitution of alyophilized powder is typically used.

As used herein, “acyl” means a carbonyl containing substituentrepresented by the formula —C(O)—R in which R is H, alkyl, a carbocycle,a heterocycle, carbocycle-substituted alkyl or heterocycle-substitutedalkyl wherein the alkyl, alkoxy, carbocycle and heterocycle are asdefined herein. Acyl groups include alkanoyl (e.g. acetyl), aroyl (e.g.benzoyl), and heteroaroyl.

“Aliphatic” means a moiety characterized by a straight or branched chainarrangement of constituent carbon atoms and may be saturated orpartially unsaturated with one or more double or triple bonds.

The term “alkyl” refers to a straight or branched hydrocarbon containing1-20 carbon atoms (e.g., C₁-C₁₀, C₁-C₆). Examples of alkyl include, butare not limited to, methyl, methylene, ethyl, ethylene, n-propyl,i-propyl, n-butyl, i-butyl, and t-butyl. Preferably, the alkyl group hasone to ten carbon atoms. More preferably, the alkyl group has one tofour carbon atoms.

The term “alkenyl” refers to a straight or branched hydrocarboncontaining 2-20 carbon atoms (e.g., C₂-C₁₀, C₂-C₆) and one or moredouble bonds. Examples of alkenyl include, but are not limited to,ethenyl, propenyl, and allyl. Preferably, the alkylene group has two toten carbon atoms. More preferably, the alkylene group has two to fourcarbon atoms.

The term “alkynyl” refers to a straight or branched hydrocarboncontaining 2-20 carbon atoms (e.g., C₂-C₁₀, C₂-C₆) and one or moretriple bonds. Examples of alkynyl include, but are not limited to,ethynyl, 1-propynyl, 1- and 2-butynyl, and 1-methyl-2-butynyl.Preferably, the alkynyl group has two to ten carbon atoms. Morepreferably, the alkynyl group has two to four carbon atoms.

The term “alkylamino” refers to an —N(R)-alkyl in which R can be H,alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl,heterocycloalkenyl, aryl, or heteroaryl.

“Alkoxy” means an oxygen moiety having a further alkyl substituent.

“Alkoxycarbonyl” means an alkoxy group attached to a carbonyl group.

“Oxoalkyl” means an alkyl, further substituted with a carbonyl group.The carbonyl group may be an aldehyde, ketone, ester, amide, acid oracid chloride.

The term “cycloalkyl” refers to a saturated hydrocarbon ring systemhaving 3 to 30 carbon atoms (e.g., C₃-C₁₂, C₃-C₈, C₃-C₆). Examples ofcycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. The term“cycloalkenyl” refers to a non-aromatic hydrocarbon ring system having 3to 30 carbons (e.g., C₃-C₁₂) and one or more double bonds. Examplesinclude cyclopentenyl, cyclohexenyl, and cycloheptenyl.

The term “heterocycloalkyl” refers to a saturated or unsaturatednonaromatic 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14membered tricyclic ring system having 1 to 4 heteroatoms (such as O, N,S, B, P, Si, or Se), which may be the same or different. Examples ofheterocycloalkyl groups include, but are not limited to, piperazinyl,pyrrolidinyl, dioxanyl, morpholinyl, and tetrahydrofuranyl.

The term “heterocycloalkenyl” refers to a nonaromatic 5-8 memberedmonocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ringsystem having one or more heteroatoms (such as O, N, S, P, B, Si, or Se)and one or more double bonds.

The term “aryl” refers to a 6-carbon monocyclic, 10-carbon bicyclic,14-carbon tricyclic aromatic ring system. Examples of aryl groupsinclude, but are not limited to, phenyl, naphthyl, and anthracenyl.

The term “heteroaryl” refers to an aromatic 5-8 membered monocyclic,8-12 membered bicyclic, or 11-14 membered tricyclic ring system havingone or more heteroatoms (such as O, N, S, P, or Se). Examples ofheteroaryl groups include pyridyl, furyl, imidazolyl, benzimidazolyl,pyrimidinyl, thienyl, quinolinyl, indolyl, and thiazolyl.

Alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl,heterocycloalkenyl, alkylamino, aryl, and heteroaryl mentioned aboveinclude both substituted and unsubstituted moieties. Possiblesubstituents on alkylamino, cycloalkyl, heterocycloalkyl, cycloalkenyl,heterocycloalkenyl, aryl, and heteroaryl include, but are not limitedto, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₂₀ cycloalkyl,C₃-C₂₀ cycloalkenyl, C₁-C₂₀ heterocycloalkyl, C₁-C₂₀ heterocycloalkenyl,C₁-C₁₀ alkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, amino, C₁-C₁₀alkylamino, arylamino, hydroxy, halo, oxo (O═), thioxo (S═), thio,silyl, C₁-C₁₀ alkylthio, arylthio, C₁-C₁₀ alkylsulfonyl, arylsulfonyl,acylamino, aminoacyl, aminothioacyl, amidino, mercapto, amido,thioureido, thiocyanato, sulfonamido, guanidine, ureido, cyano, nitro,acyl, thioacyl, acyloxy, carbamido, carbamyl, carboxyl, and carboxylicester. On the other hand, possible substituents on alkyl, alkenyl, oralkynyl include all of the above-recited substituents except C₁-C₁₀alkyl. Cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl,aryl, and heteroaryl can also be fused with each other.

“Amino” means a nitrogen moiety having two further substituents whereeach substituent has a hydrogen or carbon atom alpha bonded to thenitrogen. Unless indicated otherwise, the compounds of the inventioncontaining amino moieties may include protected derivatives thereof.Suitable protecting groups for amino moieties include acetyl,tert-butoxycarbonyl, benzyloxycarbonyl, and the like.

“Aromatic” means a moiety wherein the constituent atoms make up anunsaturated ring system, all atoms in the ring system are sp2 hybridizedand the total number of pi electrons is equal to 4n+2. An aromatic ringmay be such that the ring atoms are only carbon atoms or may includecarbon and non-carbon atoms (see Heteroaryl).

“Carbamoyl” means the radical —OC(O)NR_(a)R_(b) where R_(a) and R_(b)are each independently two further substituents where a hydrogen orcarbon atom is alpha to the nitrogen. It is noted that carbamoylmoieties may include protected derivatives thereof. Examples of suitableprotecting groups for carbamoyl moieties include acetyl,tert-butoxycarbonyl, benzyloxycarbonyl, and the like. It is noted thatboth the unprotected and protected derivatives fall within the scope ofthe invention.

“Carbonyl” means the radical —C(O)—. It is noted that the carbonylradical may be further substituted with a variety of substituents toform different carbonyl groups including acids, acid halides, amides,esters, and ketones.

“Carboxy” means the radical —C(O)O—. It is noted that compounds of theinvention containing carboxy moieties may include protected derivativesthereof, i.e., where the oxygen is substituted with a protecting group.Suitable protecting groups for carboxy moieties include benzyl,tert-butyl, and the like.

“Cyano” means the radical —CN.

“Formyl” means the radical —CH═O.

“Formimino” means the radical —HC═NH.

“Halo” means fluoro, chloro, bromo or iodo.

“Halo-substituted alkyl”, as an isolated group or part of a largergroup, means “alkyl” substituted by one or more “halo” atoms, as suchterms are defined in this Application. Halo-substituted alkyl includeshaloalkyl, dihaloalkyl, trihaloalkyl, perhaloalkyl and the like.

“Hydroxy” means the radical —OH.

“Imine derivative” means a derivative comprising the moiety —C(═NR)—,wherein R comprises a hydrogen or carbon atom alpha to the nitrogen.

“Isomers” mean any compound having identical molecular formulae butdiffering in the nature or sequence of bonding of their atoms or in thearrangement of their atoms in space.

Isomers that differ in the arrangement of their atoms in space aretermed “stereoisomers.” Stereoisomers that are not mirror images of oneanother are termed “diastereomers” and stereoisomers that arenonsuperimposable mirror images are termed “enantiomers” or sometimes“optical isomers.” A carbon atom bonded to four nonidenticalsubstituents is termed a “chiral center.” A compound with one chiralcenter has two enantiomeric forms of opposite chirality. A mixture ofthe two enantiomeric forms is termed a “racemic mixture.”

“Nitro” means the radical —NO₂.

“Protected derivatives” means derivatives of compounds in which areactive site are blocked with protecting groups. Protected derivativesare useful in the preparation of pharmaceuticals or in themselves may beactive as inhibitors. A comprehensive list of suitable protecting groupscan be found in T. W. Greene, Protecting Groups in Organic Synthesis,3rd edition, Wiley & Sons, 1999.

The term “substituted” means that an atom or group of atoms has replacedhydrogen as the substituent attached to another group. For aryl andheteroaryl groups, the term “substituted” refers to any level ofsubstitution, namely mono-, di-, tri-, tetra-, or penta-substitution,where such substitution is permitted. The substituents are independentlyselected, and substitution may be at any chemically accessible position.The term “unsubstituted” means that a given moiety may consist of onlyhydrogen substituents through available valencies (unsubstituted).

If a functional group is described as being “optionally substituted,”the function group may be either (1) not substituted, or (2)substituted. If a carbon of a functional group is described as beingoptionally substituted with one or more of a list of substituents, oneor more of the hydrogen atoms on the carbon (to the extent there areany) may separately and/or together be replaced with an independentlyselected optional substituent.

“Sulfide” means —S—R wherein R is H, alkyl, carbocycle, heterocycle,carbocycloalkyl or heterocycloalkyl. Particular sulfide groups aremercapto, alkylsulfide, for example methylsulfide (—S-Me); arylsulfide,e.g., phenylsulfide; aralkylsulfide, e.g., benzylsulfide.

“Sulfinyl” means the radical —S(O)—. It is noted that the sulfinylradical may be further substituted with a variety of substituents toform different sulfinyl groups including sulfinic acids, sulfinamides,sulfinyl esters, and sulfoxides.

“Sulfonyl” means the radical —S(O)(O)—. It is noted that the sulfonylradical may be further substituted with a variety of substituents toform different sulfonyl groups including sulfonic acids, sulfonamides,sulfonate esters, and sulfones.

“Thiocarbonyl” means the radical —C(S)—. It is noted that thethiocarbonyl radical may be further substituted with a variety ofsubstituents to form different thiocarbonyl groups including thioacids,thioamides, thioesters, and thioketones.

“Animal” includes humans, non-human mammals (e.g., non-human primates,rodents, mice, rats, hamsters, dogs, cats, rabbits, cattle, horses,sheep, goats, swine, deer, and the like) and non-mammals (e.g., birds,and the like).

“Bioavailability” as used herein is the fraction or percentage of anadministered dose of a drug or pharmaceutical composition that reachesthe systemic circulation intact. In general, when a medication isadministered intravenously, its bioavailability is 100%. However, when amedication is administered via other routes (e.g., orally), itsbioavailability decreases (e.g., due to incomplete absorption andfirst-pass metabolism). Methods to improve the bioavailability includeprodrug approach, salt synthesis, particle size reduction, complexation,change in physical form, solid dispersions, spray drying, and hot-meltextrusion.

“Disease” specifically includes any unhealthy condition of an animal orpart thereof and includes an unhealthy condition that may be caused by,or incident to, medical or veterinary therapy applied to that animal,i.e., the “side effects” of such therapy.

“Pharmaceutically acceptable” means that which is useful in preparing apharmaceutical composition that is generally safe, non-toxic and neitherbiologically nor otherwise undesirable and includes that which isacceptable for veterinary use as well as human pharmaceutical use.

“Pharmaceutically acceptable salts” means organic or inorganic salts ofcompounds of the present invention which are pharmaceuticallyacceptable, as defined above, and which possess the desiredpharmacological activity. Such salts include acid addition salts formedwith inorganic acids, or with organic acids. Pharmaceutically acceptablesalts also include base addition salts which may be formed when acidicprotons present are capable of reacting with inorganic or organic bases.Exemplary salts include, but are not limited, to sulfate, citrate,acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate,phosphate, acid phosphate, isonicotinate, lactate, salicylate, acidcitrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate,succinate, maleate, gentisinate, fumarate, gluconate, glucuronate,saccharate, formate, benzoate, glutamate, methanesulfonate “mesylate,”ethanesulfonate, benzenesulfonate, p-toluenesulfonate, pamoate (i.e.,1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts, alkali metal (e.g.,sodium and potassium) salts, alkaline earth metal (e.g., magnesium)salts, and ammonium salts. A pharmaceutically acceptable salt mayinvolve the inclusion of another molecule such as an acetate ion, asuccinate ion or other counter ion. The counter ion may be any organicor inorganic moiety that stabilizes the charge on the parent compound.Furthermore, a pharmaceutically acceptable salt may have more than onecharged atom in its structure. Instances where multiple charged atomsare part of the pharmaceutically acceptable salt can have multiplecounter ions. Hence, a pharmaceutically acceptable salt can have one ormore charged atoms and/or one or more counter ion.

“Pharmacophore,” as defined by The International Union of Pure andApplied Chemistry, is an ensemble of steric and electronic features thatis necessary to ensure the optimal supramolecular interactions with aspecific biological target and to trigger (or block) its biologicalresponse. For example, Camptothecin is the pharmacophore of the wellknown drug topotecan and irinotecan. Mechlorethamine is thepharmacophore of a list of widely used nitrogen mustard drugs likeMelphalan, Cyclophosphamide, Bendamustine, and so on.

“Prodrug” means a compound that is convertible in vivo metabolicallyinto an active pharmaceutical according to the present invention. Forexample, an inhibitor comprising a hydroxyl group may be administered asan ester that is converted by hydrolysis in vivo to the hydroxylcompound.

“Stability” in general refers to the length of time a drug retains itsproperties without loss of potency. Sometimes this is referred to asshelf life. Factors affecting drug stability include, among otherthings, the chemical structure of the drug, impurity in the formulation,pH, moisture content, as well as environmental factors such astemperature, oxidization, light, and relative humidity. Stability can beimproved by providing suitable chemical and/or crystal modifications(e.g., surface modifications that can change hydration kinetics;different crystals that can have different properties), excipients(e.g., anything other than the active substance in the dosage form),packaging conditions, storage conditions, etc.

“Therapeutically effective amount” of a composition described herein ismeant an amount of the composition which confers a therapeutic effect onthe treated subject, at a reasonable benefit/risk ratio applicable toany medical treatment. The therapeutic effect may be objective (i.e.,measurable by some test or marker) or subjective (i.e., subject gives anindication of or feels an effect). An effective amount of thecomposition described above may range from about 0.1 mg/kg to about 500mg/kg, preferably from about 0.2 to about 50 mg/kg. Effective doses willalso vary depending on route of administration, as well as thepossibility of co-usage with other agents. It will be understood,however, that the total daily usage of the compositions of the presentinvention will be decided by the attending physician within the scope ofsound medical judgment. The specific therapeutically effective doselevel for any particular patient will depend upon a variety of factorsincluding the disorder being treated and the severity of the disorder;the activity of the specific compound employed; the specific compositionemployed; the age, body weight, general health, sex and diet of thepatient; the time of administration, route of administration, and rateof excretion of the specific compound employed; the duration of thetreatment; drugs used in combination or contemporaneously with thespecific compound employed; and like factors well known in the medicalarts.

As used herein, the term “treating” refers to administering a compoundto a subject that has a neoplastic or immune disorder, or has a symptomof or a predisposition toward it, with the purpose to cure, heal,alleviate, relieve, alter, remedy, ameliorate, improve, or affect thedisorder, the symptoms of or the predisposition toward the disorder.

The term “an effective amount” refers to the amount of the active agentthat is required to confer the intended therapeutic effect in thesubject. Effective amounts may vary, as recognized by those skilled inthe art, depending on route of administration, excipient usage, and thepossibility of co-usage with other agents.

A “subject” refers to a human and a non-human animal. Examples of anon-human animal include all vertebrates, e.g., mammals, such asnon-human primates (particularly higher primates), non-human mammal,dog, rodent (e.g., mouse or rat), guinea pig, cat, and non-mammals, suchas birds, amphibians, reptiles, etc. In a preferred embodiment, thesubject is a human. In another embodiment, the subject is anexperimental animal or animal suitable as a disease model.

“Combination therapy” includes the administration of the subjectcompounds of the present invention in further combination with otherbiologically active ingredients (such as, but not limited to, a secondand different antineoplastic agent) and non-drug therapies (such as, butnot limited to, surgery or radiation treatment). For instance, thecompounds of the invention can be used in combination with otherpharmaceutically active compounds, or non-drug therapies, preferablycompounds that are able to enhance the effect of the compounds of theinvention. The compounds of the invention can be administeredsimultaneously (as a single preparation or separate preparation) orsequentially to the other therapies. In general, a combination therapyenvisions administration of two or more drugs/treatments during a singlecycle or course of therapy.

In one embodiment, the compounds of the invention are administered incombination with one or more of traditional chemotherapeutic agents. Thetraditional chemotherapeutic agents encompass a wide range oftherapeutic treatments in the field of oncology. These agents areadministered at various stages of the disease for the purposes ofshrinking tumors, destroying remaining cancer cells left over aftersurgery, inducing remission, maintaining remission and/or alleviatingsymptoms relating to the cancer or its treatment. Examples of suchagents include, but are not limited to, alkylating agents such asNitrogen Mustards (e.g., Bendamustine, Cyclophosphamide, Melphalan,Chlorambucil, Isofosfamide), Nitrosureas (e.g., Carmustine, Lomustineand Streptozocin), ethylenimines (e.g., thiotepa, hexamethylmelanine),Alkylsulfonates (e.g., Busulfan), Hydrazines and Triazines (e.g.,Altretamine, Procarbazine, Dacarbazine and Temozolomide), and platinumbased agents (e.g., Carboplatin, Cisplatin, and Oxaliplatin); plantalkaloids such as Podophyllotoxins (e.g., Etoposide and Tenisopide),Taxanes (e.g., Paclitaxel and Docetaxel), Vinca alkaloids (e.g.,Vincristine, Vinblastine and Vinorelbine); anti-tumor antibiotics suchas Chromomycins (e.g., Dactinomycin and Plicamycin), Anthracyclines(e.g., Doxorubicin, Daunorubicin, Epirubicin, Mitoxantrone, andIdarubicin), and miscellaneous antibiotics such as Mitomycin andBleomycin; anti-metabolites such as folic acid antagonists (e.g.,Methotrexate), pyrimidine antagonists (e.g., 5-Fluorouracil, Foxuridine,Cytarabine, Capecitabine, and Gemcitabine), purine antagonists (e.g.,6-Mercaptopurine and 6-Thioguanine) and adenosine deaminase inhibitors(e.g., Cladribine, Fludarabine, Nelarabine and Pentostatin);topoisomerase inhibitors such as topoisomerase I inhibitors(Topotecan,Irinotecan), topoisomerase II inhibitors (e.g., Amsacrine, Etoposide,Etoposide phosphate, Teniposide), and miscellaneous anti-neoplasticssuch as ribonucleotide reductase inhibitors (Hydroxyurea),adrenocortical steroid inhibitor (Mitotane), anti-microtubule agents(Estramustine), and retinoids (Bexarotene, Isotretinoin, Tretinoin(ATRA).

In one aspect of the invention, the compounds may be administered incombination with one or more targeted anti-cancer agents that modulateprotein kinases involved in various disease states. Examples of suchkinases may include, but are not limited ABL1, ABL2/ARG, ACK1, AKT1,AKT2, AKT3, ALK, ALK1/ACVRL1, ALK2/ACVR1, ALK4/ACVR1B, ALK5/TGFBR1,ALK6/BMPR1B, AMPK(A1/B/G1), AMPK(A1/B1/G2), AMPK(A1/B1/G3),AMPK(A1/B2/G1), AMPK(A2/Bh/G1), AMPK(A2/B2/G1), AMPK(A2/B2/G2), ARAF,ARK5/NUAK1, ASK1/MAP3K5, ATM, Aurora A, Aurora B, Aurora C, AXL, BLK,BMPR2, BMX/ETK, BRAF, BRK, BRSK1, BRSK2, BTK, CAMK1a, CAMK1b, CAMK1d,CAMK1g, CAMKIIa, CAMKIIb, CAMKIId, CAMKIIg, CAMK4, CAMKK1, CAMKK2,CDC7-DBF4, CDK1-cyclin A, CDK1-cyclin B, CDK1-cyclin E, CDK2-cyclin A,CDK2-cyclin A1, CDK2-cyclin E, CDK3-cyclin E, CDK4-cyclin D1,CDK4-cyclin D3, CDK5-p25, CDK5-p35, CDK6-cyclin D1, CDK6-cyclin D3,CDK7-cyclin H, CDK9-cyclin K, CDK9-cyclin T1, CHK1, CHK2, CK1a1, CK1d,CK1epsilon, CK1g1, CK1g2, CK1g3, CK2a, CK2a2, c-KIT, CLK1, CLK2, CLK3,CLK4, c-MER, c-MET, COT1/MAP3K8, CSK, c-SRC, CSF1R, CTK/MATK, DAPK1,DAPK2, DCAMKL1, DCAMKL2, DDR1, DDR2, DLK/MAP3K12, DMPK, DMPK2/CDC42BPG,DNA-PK, DRAK1/STK17A, DYRK1/DYRK1A, DYRK1B, DYRK2, DYRK3, DYRK4, EEF2K,EGFR, EIF2AK1, EIF2AK2, EIF2AK3, EIF2AK4/GCN2, EPHA1, EPHA2, EPHA3,EPHA4, EPHA5, EPHA6, EPHA7, EPHA8, EPHB1, EPHB2, EPHB3, EPHB4,ERBB2/HER2, ERBB4/HER4, ERK1/MAPK3, ERK2/MAPK1, ERK5/MAPK7, FAK/PTK2,FER, FES/FPS, FGFR1, FGFR2, FGFR3, FGFR4, FGR, FLT1/VEGFR1, FLT3,FLT4/VEGFR3, FMS, FRK/PTK5, FYN, GCK/MAP4K2, GRK1, GRK2, GRK3, GRK4,GRK5, GRK6, GRK7, GSK3a, GSK3b, Haspin, HCK, HGK/MAP4K4, HIPK1, HIPK2,HIPK3, HIPK4, HPK1/MAP4K1, IGF1R, IKKa/CHUK, IKKb/IKBKB, IKKe/IKBKE, IR,IRAK1, IRAK4, IRR/INSRR, ITK, JAK1, JAK2, JAK3, JNK1, JNK2, JNK3,KDRNEGFR2, KHS/MAP4K5, LATS1, LATS2, LCK, LCK2/ICK, LKB1, LIMK1,LOK/STK10, LRRK2, LYN, LYNB, MAPKAPK2, MAPKAPK3, MAPKAPK5/PRAK, MARK1,MARK2/PAR-1Ba, MARK3, MARK4, MEK1, MEK2, MEKK1, MEKK2, MEKK3, MELK,MINK/MINK1, MKK4, MKK6, MLCK/MYLK, MLCK2/MYLK2, MLK1/MAP3K9,MLK2/MAP3K10, MLK3/MAP3K11, MNK1, MNK2, MRCKa/, CDC42BPA, MRCKb/,CDC42BPB, MSK1/RPS6KA5, MSK2/RPS6KA4, MSSK1/STK23, MST1/STK4, MST2/STK3,MST3/STK24, MST4, mTOR/FRAP1, MUSK, MYLK3, MYO3b, NEK1, NEK2, NEK3,NEK4, NEK6, NEK7, NEK9, NEK11, NIK/MAP3K14, NLK, OSR1/OXSR1,P38a/MAPK14, P38b/MAPK11, P38d/MAPK13, P38g/MAPK12, P70S6K/RPS6KB1,p70S6Kb/, RPS6KB2, PAK1, PAK2, PAK3, PAK4, PAK5, PAK6, PASK, PBK/TOPK,PDGFRa, PDGFRb, PDK1/PDPK1, PDK1/PDHK1, PDK2/PDHK2, PDK3/PDHK3,PDK4/PDHK4, PHKg1, PHKg2, PI3Ka, (p110a/p85a), PI3Kb, (p110b/p85a),PI3Kd, (p110d/p85a), PI3Kg(p120g), PIM1, PIM2, PIM3, PKA, PKAcb, PKAcg,PKCa, PKCb1, PKCb2, PKCd, PKCepsilon, PKCeta, PKCg, PKCiota,PKCmu/PRKD1, PKCnu/PRKD3, PKCtheta, PKCzeta, PKD2/PRKD2, PKG1a, PKG1b,PKG2/PRKG2, PKN1/PRK1, PKN2/PRK2, PKN3/PRK3, PLK1, PLK2, PLK3, PLK4/SAK,PRKX, PYK2, RAF1, RET, RIPK2, RIPK3, RIPK5, ROCK1, ROCK2, RON/MST1R,ROS/ROS1, RSK1, RSK2, RSK3, RSK4, SGK1, SGK2, SGK3/SGKL, SIK1, SIK2,SLK/STK2, SNARK/NUAK2, SRMS, SSTK/TSSK6, STK16, STK22D/TSSK1,STK25/YSK1, STK32b/YANK2, STK32c/YANK3, STK33, STK38/NDR1, STK38IUNDR2,STK39/STLK3, SRPK1, SRPK2, SYK, TAK1, TAOK1, TAOK2/TAO1, TAOK3/JIK,TBK1, TEC, TESK1, TGFBR2, TIE2/TEK, TLK1, TLK2, TNIK, TNK1, TRKA, TRKB,TRKC, TRPM7/CHAK1, TSSK2, TSSK3/STK22C, TTBK1, TTBK2, TTK, TXK,TYK1/LTK, TYK2, TYRO3/SKY, ULK1, ULK2, ULK3, VRK1, VRK2, WEEl, WNK1,WNK2, WNK3, YES/YES1, ZAK/MLTK, ZAP70, ZIPK/DAPK3, KINASE, MUTANTS, ABL1(E255K), ABL1 (F317I), ABL1 (G250E), ABL1 (H396P), ABL1 (M351T), ABL1(Q252H), ABL1 (T315I), ABL1 (Y253F), ALK (C1156Y), ALK(L1196M), ALK(F1174L), ALK (R1275Q), BRAF(V599E), BTK(E41K), CHK2 (I157T),c-Kit(A829P), c-KIT(D816H), c-KIT(D816V), c-Kit(D820E), c-Kit(N822K),C-Kit (T670I), c-Kit(V559D), c-Kit(V559DN654A), c-Kit(V559D/T670I),C-Kit (V560G), c-KIT(V654A), C-MET(D1228H), C-MET(D1228N),C-MET(F1200I), c-MET(M1250T), C-MET(Y1230A), C-MET(Y1230C),C-MET(Y1230D), C-MET(Y1230H), c-Src(T341M), EGFR(G719C), EGFR(G719S),EGFR(L858R), EGFR(L861Q), EGFR(T790M), EGFR, (L858R,T790M),EGFR(d746-750/T790M), EGFR(d746-750), EGFR(d747-749/A750P),EGFR(d747-752/P753S), EGFR(d752-759), FGFR1 (V561M), FGFR2 (N549H),FGFR3 (G697C), FGFR3 (K650E), FGFR3 (K650M), FGFR4 (N535K), FGFR4(V550E), FGFR4 (V550L), FLT3 (D835Y), FLT3 (ITD), JAK2 (V617F), LRRK2(G2019S), LRRK2 (I2020T), LRRK2 (R1441C), p38a(T106M), PDGFRa(D842V),PDGFRa(T674I), PDGFRa(V561D), RET(E762Q), RET(G691S), RET(M918T),RET(R749T), RET(R813Q), RET(V804L), RET(V804M), RET(Y79IF), TIF2(R849W), TIF2 (Y897S), and TIF2 (Y1108F).

In another aspect of the invention, the subject compounds may beadministered in combination with one or more targeted anti-cancer agentsthat modulate non-kinase biological targets, pathway, or processes. Suchtargets pathways, or processes include but not limited to heat shockproteins (e.g. HSP90), poly-ADP (adenosine diphosphate)-ribosepolymerase (PARP), hypoxia-inducible factors (HIF), proteasome,Wnt/Hedgehog/Notch signaling proteins, TNF-alpha, matrixmetalloproteinase, farnesyl transferase, apoptosis pathway (e.g. Bcl-xL,Bcl-2, Bcl-w), histone deacetylases (HDAC), histone acetyltransferases(HAT), and methyltransferase (e.g. histone lysine methyltransferases,histone arginine methyltransferase, DNA methyltransferase, etc), andother immunotherapies(e.g. anti-PD1, anti-PDL1, anti-CTLA4, CAR-T, IDO,A2A antagonist etc).

In another aspect of the invention, the compounds of the invention areadministered in combination with one or more of other anti-cancer agentsthat include, but are not limited to, gene therapy, RNAi cancer therapy,chemoprotective agents (e.g., amfostine, mesna, and dexrazoxane),antibody conjugate(e.g. brentuximab vedotin, ibritumomab tioxetan),cancer immunotherapy such as Interleukin-2, cancer vaccines(e.g.,sipuleucel-T) or monoclonal antibodies (e.g., Bevacizumab, Alemtuzumab,Rituximab, Trastuzumab, etc).

In another aspect of the invention, the subject compounds areadministered in combination with radiation therapy or surgeries.Radiation is commonly delivered internally (implantation of radioactivematerial near cancer site) or externally from a machine that employsphoton (x-ray or gamma-ray) or particle radiation. Where the combinationtherapy further comprises radiation treatment, the radiation treatmentmay be conducted at any suitable time so long as a beneficial effectfrom the co-action of the combination of the therapeutic agents andradiation treatment is achieved. For example, in appropriate cases, thebeneficial effect is still achieved when the radiation treatment istemporally removed from the administration of the therapeutic agents,perhaps by days or even weeks.

In certain embodiments, the compounds of the invention are administeredin combination with one or more of radiation therapy, surgery, oranti-cancer agents that include, but are not limited to, DNA damagingagents, anti-metabolites, topoisomerase inhibitors, anti-microtubuleagents, kinase inhibitors, epigenetic agents, HSP90 inhibitors, PARPinhibitors, and antibodies targeting VEGF, HER2, EGFR, CD50, CD20, CD30,CD33, etc.

In certain embodiments, the compounds of the invention are administeredin combination with one or more of abarelix, abiraterone acetate,aldesleukin, alemtuzumab, altretamine, anastrozole, asparaginase,bendamustine, bevacizumab, bexarotene, bicalutamide, bleomycin,bortezombi, brentuximab vedotin, busulfan, capecitabine, carboplatin,carmustine, cetuximab, chlorambucil, cisplatin, cladribine, clofarabine,clomifene, crizotinib, cyclophosphamide, dasatinib, daunorubicinliposomal, decitabine, degarelix, denileukin diftitox, denileukindiftitox, denosumab, docetaxel, doxorubicin, doxorubicin liposomal,epirubicin, eribulin mesylate, erlotinib, estramustine, etoposidephosphate, everolimus, exemestane, fludarabine, fluorouracil,fotemustine, fulvestrant, gefitinib, gemcitabine, gemtuzumab ozogamicin,goserelin acetate, histrelin acetate, hydroxyurea, ibritumomab tiuxetan,idarubicin, ifosfamide, imatinib mesylate, interferon alfa 2a,ipilimumab, ixabepilone, lapatinib ditosylate, lenalidomide, letrozole,leucovorin, leuprolide acetate, levamisole, lomustine, mechlorethamine,melphalan, methotrexate, mitomycin C, mitoxantrone, nelarabine,nilotinib, oxaliplatin, paclitaxel, paclitaxel protein-bound particle,pamidronate, panitumumab, pegaspargase, peginterferon alfa-2b,pemetrexed disodium, pentostatin, raloxifene, rituximab, sorafenib,streptozocin, sunitinib maleate, tamoxifen, temsirolimus, teniposide,thalidomide, toremifene, tositumomab, trastuzumab, tretinoin,uramustine, vandetanib, vemurafenib, vinorelbine, zoledronate,pembrolizumab, nivolumab, atezolizumab, durvalumab, avelumab, astisagenlecleucel, axicabtagene ciloleucel, radiation therapy, orsurgery.

The invention further provides methods for the prevention or treatmentof a neoplastic disease or autoimmune disease. In one embodiment, theinvention relates to a method of treating a neoplastic disease orautoimmune disease, in a subject in need of treatment comprisingadministering to said subject a therapeutically effective amount of acompound of the invention. In one embodiment, the invention furtherprovides for the use of a compound of the invention in the manufactureof a medicament for halting or decreasing a neoplastic disease orautoimmune disease.

In certain embodiments, the neoplastic disease is a lung cancer, headand neck cancer, central nervous system cancer, prostate cancer,testicular cancer, colorectal cancer, pancreatic cancer, liver cancer,stomach cancer, biliary tract cancer, esophageal cancer,gastrointestinal stromal tumor, breast cancer, cervical cancer, ovariancancer, uterine cancer, leukemia, lymphomas, multiple myeloma, melanoma,basal cell carcinoma, squamous cell carcinoma, bladder cancer, renalcancer, sarcoma, mesothelioma, thymoma, myelodysplastic syndrome, ormyeloproliferative disease.

The autoimmune diseases that can be affected using compounds andcompositions according to the invention include, but are not limited toallergy, Alzheimer's disease, acute disseminated encephalomyelitis,Addison's disease, ankylosing spondylitis, antiphospholipid antibodysyndrome, asthma, atherosclerosis, autoimmune hemolytic anemia,autoimmune hemolytic and thrombocytopenic states, autoimmune hepatitis,autoimmune inner ear disease, bullous pemphigoid, coeliac disease,chagas disease, chronic obstructive pulmonary disease, chronicIdiopathic thrombocytopenic purpura (ITP), churg-strauss syndrome,Crohn's disease, dermatomyositis, diabetes mellitus type 1,endometriosis, Goodpasture's syndrome (and associated glomerulonephritisand pulmonary hemorrhage), graves' disease, guillain-barrd syndrome,hashimoto's disease, hidradenitis suppurativa, idiopathicthrombocytopenic purpura, interstitial cystitis, irritable bowelsyndrome, lupus erythematosus, morphea, multiple sclerosis, myastheniagravis, narcolepsy, neuromyotonia, Parkinson's disease, pemphigusvulgaris, pernicious anaemia, polymyositis, primary biliary cirrhosis,psoriasis, psoriatic arthritis, rheumatoid arthritis, schizophrenia,septic shock, scleroderma, Sjogren's disease, systemic lupuserythematosus (and associated glomerulonephritis), temporal arteritis,tissue graft rejection and hyperacute rejection of transplanted organs,vasculitis (ANCA-associated and other vasculitides), vitiligo, andwegener's granulomatosis.

It should be understood that the invention is not limited to theparticular embodiments shown and described herein, but that variouschanges and modifications may be made without departing from the spiritand scope of the invention as defined by the claims.

The compounds according to the present invention may be synthesizedaccording to a variety of schemes. Necessary starting materials may beobtained by standard procedures of organic chemistry. The compounds andprocesses of the present invention will be better understood inconnection with the following representative synthetic schemes andexamples, which are intended as an illustration only and not limiting ofthe scope of the invention. Various changes and modifications to thedisclosed embodiments will be apparent to those skilled in the art andsuch changes and modifications including, without limitation, thoserelating to the chemical structures, substituents, derivatives, and/ormethods of the invention may be made without departing from the spiritof the invention and the scope of the appended claims.

A typical approach to synthesize of the intermediate is

-   described in Scheme 1 below: R₁, R₂, m, and n, in general Scheme 1    are the same as those described in the Summary section above.

In Scheme 1, the appropriate ketone starting material 1-1 can react withtribromophosphine to form the aldehyde intermediate 1-2, which cancouple with Boc-protected piperazine to form the intermediate 1-3. Afterthat, 1-3 will couple with appropriate phenylboronic acid via a Suzukireaction to form intermediate 1-4, followed by a de-boc process to yieldkey intermediate 1-5.

A typical approach to synthesize of the intermediate

in which R₅ is NO₂ is described in Scheme 2 below. R₄, R₅, L, and R₆, ingeneral Scheme 2 are the same as those described in the Summary sectionabove.

In Scheme 2, the starting material 2-1 reacts with appropriate alcoholor amine will yield 2-2.

A typical approach to synthesize of

is described in Scheme 3 below. In Scheme 3, the intermediate 3-6 iscommercially available. Protection of free NH of 3-6 yields 3-7, whichis converted to 3-8 via Buckwald coupling and nucleophilic aromaticsubstitution. Double deprotection gives 3-9, which is O-alkylated toafford ester 3-10 and subsequently undergoes ring closure to form 3-11.Reduction of 3-11 produces intermediate 3-12.

A typical approach to synthesize of

in which R₉ and k are the same as those described in the Summary sectionabove is described in Scheme 3-2 (Method A), 3-3 (Method B), 3-4 (MethodC) below.

Method A

In Scheme 3-2, the protection of free NH of commercially availablestarting material 3-2-1 yields 3-2-2, which is converted to 3-2-3 vianucleophilic aromatic substitution (PG=Boc, Ts). 3-2-3 undergoes ringclosure via Buchwald coupling to give 3-2-4, which is deprotected toafford intermediate 3-2-5.

Method B

In Scheme 3-3, the protection of free NH of commercially availablestarting material 3-3-1 yields 3-3-2, which is converted to 3-3-3 vianucleophilic aromatic substitution. Deprotection affords 3-3-4 andsubsequently, Buchwald ring closure to produce intermediate 3-3-5.

Method C

In Scheme 3-4, the protection of free NH of commercially availablestarting material 3-4-1 yields 3-4-2, which is converted to 3-4-4 vianucleophilic aromatic substitution and followed by Buchwald or Ullmanncoupling. Mitsunobu reaction of 3-4-4 gives 3-4-5 which is deprotectedto produce intermediate 3-4-6.

A typical approach to synthesize of

in which R₉ and k are the same as those described in the Summary sectionabove is described in Scheme 3-5 (Method A), below.

Method A

In Scheme 3-5, the protection of free NH of commercially availablestarting material 3-5-1 yields 3-5-2, which is converted to 3-5-3 vianucleophilic aromatic substitution (PG=Boc, Ts). 3-5-3 undergoes ringclosure via Buchwald coupling to give 3-5-4, which is deprotected toafford intermediate 3-5-5.

A typical approach to synthesize of

in which R₉ and k are the same as those described in the Summary sectionabove is described in Scheme 3-8 below.

In Scheme 3-8, the thioether N-oxidation of 3-8-1 (which is synthesizedfrom Scheme 3-5, 3-6, 3-7) reacts with m-CPBA to form 3-8-2.

The intermediates of

in which and k are the same as those described in the Summary sectionabove can be made by routes similar to Scheme 3, Scheme 3-2 (Method A),3-3 (Method B), 3-4 (Method C), Scheme 3-5, and Scheme 3-8.

Other intermediates of

in which Q is a 6 membered ring, R₇, R₈, R₉, Y, W, W₁, and k are thesame as those described in the Summary section above can be made byroutes similar to Scheme 3, Scheme 3-2 (Method A), 3-3 (Method B), 3-4(Method C), Scheme 3-5, and Scheme 3-8.

A typical approach to synthesize of Formula (D) compounds in which Z₂ isO is described in Scheme I:

In Scheme I, the intermediate 1-5 undergoes nucleophilic aromaticsubstitution with selected p-fluoro-2-bromo-benzoate to give I-2.Buckwald coupling of I-2 with appropriate amine intermediate yields I-3.I-3 is deprotected sequentially with TFA to remove SEM group and NaOH toremove ester group, producing free carboxylic acid intermediate I-5.Coupling of I-5 with 2-2 affords final product with Formula (D).

The compound of Formula (D) with different Z can be prepared by themethod similar to the General Scheme I by using appropriate staringmaterials and intermediates.

The compound of Formula (C), (B), and (A) can be prepared by the methodsimilar to the General Scheme I by using appropriate staring materialsand intermediates.

The compounds and processes of the present invention will be betterunderstood in connection with the following examples, which are intendedas an illustration only and not limiting of the scope of the invention.Various changes and modifications to the disclosed embodiments will beapparent to those skilled in the art and such changes and modificationsincluding, without limitation, those relating to the chemicalstructures, substituents, derivatives, formulations and/or methods ofthe invention may be made without departing from the spirit of theinvention and the scope of the appended claims.

Where NMR data are presented, ¹H spectra were obtained on XL400 (400MHz) and are reported as ppm down field from Me₄Si with number ofprotons, multiplicities, and coupling constants in Hertz indicatedparenthetically. Where HPLC data are presented, analyses were performedusing an Agilent 1100 system. Where LC/MS data are presented, analyseswere performed using an Applied Biosystems API-100 mass spectrometer andShimadzu SCL-10A LC column:

Example 1-1: Preparation of1-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazine

Synthesis of 2-bromo-4,4-dimethylcyclohex-1-enecarbaldehyde 2: Asolution of anhydrous chloroform (57 ml) and anhydrousN,N-dimethylformamide (9 mL) was cooled to ˜3° C. (internal temperature)under nitrogen before phosphorus tribromide (10 mL, 0.1 mol) wasintroduced dropwise at a rate so that the reaction was maintained at ˜3°C. After the addition was complete the reaction was allowed to warmslowly to ˜10° C. and then the temperature was raised to 70° C. where itwas maintained for 30 min. The reaction was cooled to rt and3,3-dimethylcyclohexanone 1 (5 g, 0.04 mol) was added slowly over 20min. After the addition was complete the reaction was warmed to 70° C.and it was stirred for 1.5 h. The mixture was then cooled to 0° C. and asolution of 4M sodium acetate (53 ml) was added slowly. The pH of theresulting solution was adjusted to ˜7 using a solution of 5M NaOH andthe mixture was then extracted with heptanes (100 mL×3). The combinedorganic fractions were dried (Na₂SO₄), filtered and concentrated underreduced pressure to give 2-bromo-4,4-dimethylcyclohex-1-enecarbaldehyde2 (4 g, 49%) as a yellow oil.

Synthesis of 2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enecarbaldehyde3: To a degassed solution of2-bromo-4,4-dimethylcyclohex-1-enecarbaldehyde 2 (5 g, 0.023 mol) and4-chlorophenyl boronic acid (3.6 g, 0.023 mol) in 1,4-dioxane (50 mL) atrt was added a solution of 2M Na₂CO₃ (20.4 ml). Nitrogen was bubbledthrough the mixture for 2 min and then PdCl₂(dppf) (0.5 g) was added.The reaction flask was heated to 120° C. where it was maintained for 3h. After this time the suspension was cooled to rt and filtered throughCelite. The collected solids were washed with additional dichloromethaneand the combined filtrate and washings were concentrated under reducedpressure. Purification by column chromatography on silica with PE:EA=20:1 gave 2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enecarbaldehyde 3(3 g, 53%) as a white solid. MS: 249[M+H]⁺

Synthesis of (2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methanol 4:A solution of 2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enecarbaldehyde3 (20 g, 80.6 mmol) in MeOH (100 mL) was cooled to 0° C., NaBH₄ (3.1g,80.6 mmol) was added portionwise to the reaction at a rate so that thereaction was maintained at 0˜5° C. After added, the mixture was stirredfor 1 h at 0° C. Water was added slowly to the mixture and extractedwith EA (200 mL×3), the organic layer was washed with brine and driedNa₂SO₄. filtered and concentrated under reduced pressure to give(2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methanol 4 (15 g, 75%)as a white solid. MS: 233[M+H−H₂O]⁺

Synthesis of1-(2-(bromomethyl)-5,5-dimethylcyclohex-1-enyl)-4-chlorobenzene 5: Asolution of (2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methanol 4(15 g, 0.060 mol) and in Et₂O (300 ml) was cooled to 0° C. beforephosphorus tribromide (7.5 mL) was added dropwise to the mixture, afteradded, the mixture was stiffed for 1 h at 0° C. for 90 minutes. Thereaction mixture was added H₂O before being extracted with EA. Theorganic layer was washed with a saturated NaHCO₃solution and brine anddried Na₂SO₄. filtered and concentrated under reduced pressure to give1-(2-(bromomethyl)-5,5-dimethylcyclohex-1-enyl)-4-chlorobenzene 5 (18 g,96%) as a colorless oil.

Synthesis of tert-butyl4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazine-1-carboxylate—Toa solution of 1-bromo-2-(bromomethyl)-5,5-dimethylcyclohex-1-ene 5 (21g, 0.067 mol) and tert-butyl piperazine-1-carboxylate (12.4 g, 0.067mol) in dichloromethane (200 ml) at rt was added TEA (12.2 g, 0.12 mol).The reaction was stirred for 2 h. The reaction mixture was concentratedunder reduced pressure to give the crude product. Purification by columnchromatography on silica with PE:EA=20:1 provided tert-butyl4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazine-1-carboxylate6 (21 g, 75%).

Synthesis of1-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazinehydrogen chloride: To a solution of tert-butyl4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazine-1-carboxylate6 (30 g, 0.072 mol) in MeOH (20 ml) was added conc. HCl (50 mL). Thereaction was stirred for 24 hours and then concentrated under reducedpressure. A saturated solution of Na₂CO₃ was added to adjust the pH to˜8-9 and the mixture was extracted with dichloromethane (×2). Thecombined extracts were washed with brine, dried (Na₂SO₄), filtered andconcentrated under reduced pressure. The oil product was treated withMeOH/HCl(g) (3M, 500 mL) and stirred for 1 hour, then concentrated underreduced pressure to get the product1-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazinehydrogen chloride IM-14-1 (23 g, 83%). MS: 319[M+H]⁺ ¹H NMR (400 MHz,DMSO) δ 11.51 (s, 1H), 9.60 (s, 1H), 9.18 (s, 1H), 7.45 (d, J=8.2 Hz,2H), 7.15 (d, J=8.0 Hz, 2H), 3.43 (s, 8H), 2.84 (s, 2H), 2.39 (s, 2H),2.03 (s, 2H), 1.45 (t, J=6.0 Hz, 2H), 0.96 (s, 6H).

Example 1-2: Preparation of3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide

To a 500 mL three-neck RB flask equipped with a mechanical stirrer werecharged the 4-chloro-3-nitrobenzenesulfonamide (23.7 g, 100 mmol), DIPEA(12.9 g, 100 mmol), (tetrahydro-2H-pyran-4-yl)methanamine(11.5 g, 100mmol) and acetonitrile (200 mL). The reaction mixture was adjusted to aninternal temperature of 80° C. and agitated for no less than 12 hours.The product solution was cooled down to 40° C. and agitated for no lessthan 1 hour until precipitation observed. The product slurry was furthercooled to 20° C. Water (80 mL) was slowly charged over no less than 1hour, and the mixture cooled to 10° C. and agitated for no less than 2hours before collected by filtration. The wet cake was washed with 1:1mix of acetonitrile:water (40 mL). The wet cake was rinsed with water(80 mL) at 40° C. for no less than 1 hour before collected byfiltration. The wet cake was rinsed with water (20 mL), and dried at 75°C. under vacuum to give the3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide(24.5 g, 78%) as an orange solid. ¹H NMR (400 MHz, DMSO) δ 8.60 (t,J=5.9 Hz, 1H), 8.48 (d, J=2.2 Hz, 1H), 7.84 (dd, J=9.2, 2.0 Hz, 1H),7.54-7.18 (m, 3H), 3.86 (dd, J=11.3, 3.2 Hz, 2H), 3.35 (s, 2H), 3.27 (t,J=10.9 Hz, 2H), 1.92 (ddd, J=11.2, 7.4, 3.9 Hz, 1H), 1.62 (d, J=11.4 Hz,2H), 1.27 (qd, J=12.3, 4.4 Hz, 2H).

Example 1-3: Preparation of3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide

Into a 50-mL round-bottom flask, was placed(4-fluorooxan-4-yl)methanamine hydrochloride (500 mg, 2.95 mmol, 1.00equiv), 4-fluoro-3-nitrobenzene-1-sulfonamide (650 mg, 2.95 mmol, 1.00equiv), tetrahydrofuran (15 mL), Cs₂CO₃ (2.8 g, 8.59 mmol, 3.00 equiv).The resulting solution was stiffed for 14 h at 50° C. in an oil bath.The reaction mixture was cooled to room temperature. The resultingmixture was filtered and concentrated under vacuum. The residue wasapplied onto a silica gel column with ethyl acetate/petroleum ether(4:1). This resulted in 650 mg (66%) of4-[[(4-fluorooxan-4-yl)methyl]amino]-3-nitrobenzene-1-sulfonamide as ayellow solid. LCMS (ES, m/z): M+1: 334. H-NMR: (300 MHz, DMSO, ppm): δ8.58 (t, J=6.3 Hz, 1H), 8.49 (d, J=2.1 Hz, 1H), 7.90-7.80 (m, 1H), 7.44(d, J=9.3 Hz, 1H), 7.34 (s, 2H), 3.87-3.70 (m, 4H), 3.61-3.50 (m, 2H),1.95-1.70 (m, 4H).

Example 1-4: Improved method for the synthesis of6-((2-(trimethylsilyl)ethoxy)methyl)-1,2,3,6-tetrahydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazine

Into a 250-mL 3-necked round-bottom flask, was placed6-fluoropyridin-2-amine (11.2 g, 99.91 mmol, 1.00 equiv), CH₃CN (100mL), NBS (21.4 g, 120.24 mmol, 1.20 equiv). The resulting solution wasstirred for overnight at room temperature. The reaction was thenquenched by the addition of 200 mL of water. The resulting solution wasextracted with 3×100 mL of ethyl acetate and the organic layerscombined. The resulting mixture was washed with 3×100 mL of brine. Themixture was dried over anhydrous sodium sulfate, then filtered andconcentrated under vacuum. The residue was applied onto a silica gelcolumn with ethyl acetate/petroleum ether (0:1-1:5). This resulted in 12g (63%) of 5-bromo-6-fluoropyridin-2-amine as a white solid. LCMS (ES,m/z): M+1: 191, 193.

Into a 2000-mL 4-necked round-bottom flask, was placed5-bromo-6-fluoropyridin-2-amine (110 g, 575.91 mmol, 1.00 equiv) in,AcOH (1000 mL), iodo(sulfanyl)amine (142.5 g, 633.33 mmol, 1.10 equiv).The resulting solution was stirred for overnight at room temperature.The reaction was then quenched by the addition of 3000 mL of water. Thesolids were collected by filtration. This resulted in 170 g (93%) of5-bromo-6-fluoro-3-iodopyridin-2-amine as a white solid. H-NMR: (CDCl₃,300 MHz) δ: 7.98 (d, J=14.4 Hz, 1H), 4.94-5.00 (bs, 2H).

Into a 3000-mL 3-necked round-bottom flask, was placed a solution of5-bromo-6-fluoro-3-iodopyridin-2-amine (170 g, 536.45 mmol, 1.00 equiv)in tetrahydrofuran (1500 mL), CuI (10.2 g, 53.56 mmol, 0.10 equiv), TEA(500 mL), dichloropalladium; bis(triphenylphosphane) (11.2 g, 15.96mmol, 0.03 equiv), ethyl(ethynyl)dimethylsilane (63 g, 561.27 mmol, 1.20equiv). The resulting solution was stirred for 1 overnight at roomtemperature. The reaction was then quenched by the addition of 2000 mLof water. The resulting solution was extracted with 3×1000 mL of ethylacetate and the organic layers combined. The resulting mixture waswashed with 3×1000 mL of brine. The mixture was dried over anhydroussodium sulfate, then filtered and concentrated under vacuum. The residuewas applied onto a silica gel column with ethyl acetate/petroleum ether(0:1-1:1). This resulted in 120 g (78%) of5-bromo-6-fluoro-3-[2-(trimethylsilyl)ethynyl]pyridin-2-amine as yellowoil. LCMS (ES, m/z): M+1: 289, 287

Into a 2000-mL 4-necked round-bottom flask, was placed a solution of5-bromo-6-fluoro-3-[2-(trimethylsilyl)ethynyl]pyridin-2-amine (84 g,292.48 mmol, 1.00 equiv) in dichloromethane (1000 mL), pyridine (57.8 g,730.72 mmol, 2.50 equiv). This was followed by the addition of acetylchloride (50.2 g, 639.51 mmol, 2.20 equiv) dropwise with stirring at 0degree. The resulting solution was stirred for overnight at roomtemperature. The reaction was then quenched by the addition of 1000 L ofwater. The resulting mixture was washed with 2×1000 mL of water. Themixture was dried over anhydrous sodium sulfate and concentrated undervacuum. The residue was applied onto a silica gel column with ethylacetate/petroleum ether (0:1-1:10). This resulted in 80 g (83%) ofN-[5-bromo-6-fluoro-3-[2-(trimethylsilyl)ethynyl]pyridin-2-yl]acetamideas a white solid. LC-MS: (ES, m/z): M+1=331, R,T=1.669 min. Themeasurements of the retention were done with a reversed phase column(C18). Shimadzu LCMS 2020; 50*3.0 Kinetex 2.6u XB-C18, 2.6 microm;Eluent A: water (0.05% TFA); Eluent B: Acetonitrile; linear gradient

Into a 2000-mL round-bottom flask, was placed a solution ofN-[5-bromo-6-fluoro-3-[2-(trimethylsilyl)ethynyl]pyridin-2-yl]acetamide(80 g, 242.98 mmol, 1.00 equiv) in tetrahydrofuran (300 mL), TBAF(1M intetrahydrofuran) (729 mL, 3.00 equiv). The resulting solution wasstirred for 12 h at 70 degree. The reaction mixture was cooled to roomtemperature. The resulting mixture was concentrated under vacuum. Thereaction was then quenched by the addition of 500 mL of water. Theresulting solution was extracted with 3×300 mL of ethyl acetate and theorganic layers combined. The resulting mixture was washed with 3×300 mLof brine. The mixture was dried over anhydrous sodium sulfate andconcentrated under vacuum. The residue was applied onto a silica gelcolumn with ethyl acetate/petroleum ether (0:1-4:1). This resulted in 15g (29%) of 5-bromo-6-fluoro-1H-pyrrolo[2,3-b]pyridine as a white solid.LC-MS: (ES, m/z): M+1=213, R,T=1.451 min. The measurements of theretention were done with a reversed phase column (C18). Shimadzu LCMS2020; 50*3.0 Kinetex 2.6u XB-C18, 2.6 microm; Eluent A: water (0.05%TFA); Eluent B: Acetonitrile; linear gradient

Into a 250-mL 3-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen, was placed a solution of5-bromo-6-fluoro-1H-pyrrolo[2,3-b]pyridine (15 g, 69.76 mmol, 1.00equiv) in N,N-dimethylformamide (150 mL). This was followed by theaddition of sodium hydride (4.2 g, 175.00 mmol, 1.50 equiv), in portionsat 0 degree. After 0.5 h stirring, to this was added SEMCl (14 g, 84.34mmol, 1.20 equiv) dropwise with stirring at 0 degree. The resultingsolution was allowed to react, with stirring, for an additional 3 h atroom temperature. The reaction was then quenched by the addition of 300mL of water. The resulting solution was extracted with 3×200 mL of ethylacetate and the organic layers combined. The resulting mixture waswashed with 3×200 mL of brine. The mixture was dried over anhydroussodium sulfate and concentrated under vacuum. The residue was appliedonto a silica gel column with ethyl acetate/petroleum ether (0:1-1:10).This resulted in 15 g (62%) of5-bromo-6-fluoro-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridineas yellow oil. H-NMR−: (CDCl₃, 300 MHz) δ: 8.19 (d, J=8.7 Hz, 1H), 7.37(d, J=3.6 Hz, 1H), 6.54 (d, J=3.6 Hz, 1H), 5.64 (s, 2H), 3.58 (t, J=8.1Hz, 2H), 0.98-0.93 (t, J=8.1 Hz, 2H), 0.00 (s, 9H). The measurements ofthe NMR spectra were done with BrukerAvanceIII HD 300 MHz with a probehead of BBOF

Into a 250-mL round-bottom flask, was placed a solution of5-bromo-6-fluoro-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridine(6.9 g, 19.98 mmol, 1.00 equiv) in dioxane (70 mL), t-BuOK (6.84 g,60.96 mmol, 3.00 equiv), x-antphos (2.3 g, 3.98 mmol, 0.20 equiv),Pd₂(dba)₃.CHCl₃ (1.9 g, 0.10 equiv), diphenylmethanimine (4.32 g, 23.84mmol, 1.20 equiv). The resulting solution was stiffed for overnight at100° C. The resulting mixture was concentrated under vacuum. The residuewas applied onto a silica gel column with ethyl acetate/petroleum ether(0:1-1:20). This resulted in 3.6 g (crude) of6-(tert-butoxy)-N-(diphenylmethylidene)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridin-5-amineas white oil. LC-MS−: (ES, m/z): M+1=500.

Into a 50-mL round-bottom flask, was placed a solution of6-(tert-butoxy)-N-(diphenylmethylidene)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridin-5-amine(3.6 g, 7.20 mmol, 1.00 equiv) in dioxane (15 mL), 4M HCl in dioxane (20mL). The resulting solution was stirred for 2 h at room temperature. Thereaction was then quenched by the addition of 50 mL of satu. sodiumbicarbonate. The solids were collected by filtration. This resulted in 1g (50%) of5-amino-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridin-6-olas a white solid. LC-MS: (ES, m/z): M+1=280, R,T=0.811 min. Themeasurements of the retention were done with a reversed phase column(C18). Shimadzu LCMS 2020; 50*3.0 Kinetex 2.6u XB-C18, 2.6 microm;Eluent A: water (0.05% TFA); Eluent B: Acetonitrile; linear gradient

Into a 100-mL round-bottom flask, was placed a solution of5-amino-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridin-6-ol(1 g, 3.58 mmol, 1.00 equiv) in CH₃CN (50 mL), Cs₂CO₃ (1.75 g, 5.37mmol, 1.50 equiv), ethyl 2-chloroacetate (438 mg, 3.57 mmol, 1.00equiv). The resulting solution was stirred for 2 h at 70 degree. Thereaction mixture was cooled to room temperature. The reaction was thenquenched by the addition of 50 mL of water. The resulting solution wasextracted with 3×50 mL of ethyl acetate and the organic layers combined.The resulting mixture was washed with 3×50 mL of brine. The mixture wasdried over anhydrous sodium sulfate, then filtered and concentratedunder vacuum. The residue was applied onto a silica gel column withethyl acetate/petroleum ether (0:1-1:1). This resulted in 1 g (76%) ofethyl2-[(5-amino-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridin-6-yl)oxy]acetateas a white solid. LC-MS: (ES, m/z): M+1=366.

Into a 100-mL round-bottom flask, was placed a solution of ethyl2-[(5-amino-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridin-6-yl)oxy]acetate(1 g, 2.74 mmol, 1.00 equiv) in ethanol (20 mL), Cs₂CO₃ (1.78 g, 5.46mmol, 2.00 equiv). The resulting solution was stirred for overnight atreflux. The reaction mixture was cooled to room temperature. Theresulting mixture was filtered and concentrated under vacuum. Theresidue was applied onto a silica gel column with ethylacetate/petroleum ether (0:1-1:2). This resulted in 400 mg (46%) of4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazatricyclo[7.4.0.0{circumflexover ( )}[3,7]]trideca-1(9),2,5,7-tetraen-11-one as a white solid.LC-MS: (ES, m/z): M+1=320.

Into a 25-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed a solution of4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazatricyclo[7.4.0.0{circumflexover ( )}[3,7]]trideca-1(9),2,5,7-tetraen-11-one (400 mg, 1.25 mmol,1.00 equiv) in tetrahydrofuran (mL). This was followed by the additionof LiAlH₄ (95 mg, 2.50 mmol, 2.00 equiv), in portions at −78 degree. Theresulting solution was stirred for 4 h at room temperature. The reactionwas then quenched by the addition of 20 mL of water. The solids werefiltered out. The resulting solution was extracted with 3×20 mL of ethylacetate and the organic layers combined. The resulting mixture waswashed with 3×20 mL of brine. The mixture was dried over anhydroussodium sulfate and concentrated under vacuum. The residue was appliedonto a silica gel column with ethyl acetate/petroleum ether (0:1-1:1).This resulted in 180 mg (47%) of4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazatricyclo[7.4.0.0{circumflexover ( )}[3,7]]trideca-1(9),2,5,7-tetraene as brown oil. H-NMR: (CDCl₃,300 MHz) δ: 7.36 (s, 1H), 7.28 (s, 1H), 7.25 (d, J=3.3 Hz, 1H), 6.31 (d,J=3.3 Hz, 1H), 5.58 (s, 2H), 4.48-4.52 (m, 2H), 3.72-3.60 (m, 2H),3.60-3.52 (m, 2H), 0.92-0.87 (m, 2H), 0.00 (s, 9H).

Example 2: Preparation of NW-4-8 which was Disclosured in Our PreviousApplication WO/2017/132474, by Using the Intermediate of Example 1-4Above

Into a 250-mL round-bottom flask, was placed a solution of1-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazine(15.09 g, 47.32 mmol, 1.00 equiv) in DMA (150 mL), DIEA (12.9 g, 99.81mmol, 2.00 equiv), methyl 2-bromo-4-fluorobenzoate (11.6 g, 49.78 mmol,1.00 equiv). The resulting solution was stirred for 12 h at 100 degree.The reaction mixture was cooled to room temperature. The reaction wasthen quenched by the addition of 50 mL of water. The resulting solutionwas extracted with 3×100 mL of ethyl acetate and the organic layerscombined. The resulting mixture was washed with 3×100 mL of brine. Themixture was dried over anhydrous sodium sulfate, then filtered andconcentrated under vacuum. The residue was applied onto a silica gelcolumn with ethyl acetate/petroleum ether (0:1-1:5). This resulted in 7g (crude) of methyl2-bromo-4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)benzoateas yellow oil. LC-MS (ES, m/z): M+1=533, 531.

Into a 40-mL round-bottom flask, was placed a solution of4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazatricyclo[7.4.0.0{circumflexover ( )}[3,7]]trideca-1,3(7),5,8-tetraene (175 mg, 0.57 mmol, 1.00equiv) in dioxane (10 mL), Cs₂CO₃ (560 mg, 1.72 mmol, 3.00 equiv),XantPhos Pd G2 (CAS: 1375325-77-1) (53 mg, 0.06 mmol, 0.10 equiv),methyl2-bromo-4-(4-[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methylpiperazin-1-yl)benzoate(334.7 mg, 0.63 mmol, 1.10 equiv). The resulting solution was stirredfor 2 h at 110 degree. The reaction mixture was cooled to roomtemperature. The solids were filtered out. The resulting mixture wasconcentrated under vacuum. The residue was applied onto a silica gelcolumn with ethyl acetate/petroleum ether (0:1-1:3). This resulted in200 mg (46%) of methyl4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-(4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazatricyclo[7.4.0.0{circumflexover ( )}[3,7]]trideca-1,3(7),5,8-tetraen-10-yl)benzoate as yellow oil.LC-MS: (ES, m/z): M+1=756, R,T=1.252 min. The measurements of theretention were done with a reversed phase column (C18). Shimadzu LCMS2020; 50*3.0 Kinetex 2.6u XB-C18, 2.6 microm; Eluent A: water (0.05%TFA); Eluent B: Acetonitrile; linear gradient.

Into a 50-mL round-bottom flask, was placed a solution of methyl4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-(4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazatricyclo[7.4.0.0{circumflex over( )}[3,7]]trideca-1,3(7),5,8-tetraen-10-yl)benzoate (200 mg, 0.26 mmol,1.00 equiv) in tetrahydrofuran (20 mL), TBAF (3 mg, 0.01 mmol),ethane-1,2-diamine (3 mL). The resulting solution was stirred for 24 hat 60 degree. The reaction mixture was cooled to room temperature. Thereaction was then quenched by the addition of 30 mL of water. Theresulting solution was extracted with 2×30 mL of ethyl acetate and theorganic layers combined. The resulting mixture was washed with 2×30 mLof brine. The mixture was dried over anhydrous sodium sulfate andconcentrated under vacuum. The residue was applied onto a silica gelcolumn with ethyl acetate/petroleum ether (0:1-1:2). This resulted in 90mg (54%) of methyl4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[13-oxa-2,4,10-triazatricyclo[7.4.0.0{circumflexover ( )}[3,7]]trideca-1,3(7),5,8-tetraen-10-yl]benzoate as a yellowsolid. LC-MS(ES, m/z): M+1=626, R,T=1.052 min. The measurements of theretention were done with a reversed phase column (C18). Shimadzu LCMS2020; 50*3.0 Kinetex 2.6u XB-C18, 2.6 microm; Eluent A: water (0.05%TFA); Eluent B: Acetonitrile; linear gradient.

Into a 8-mL round-bottom flask, was placed a solution of methyl4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[13-oxa-2,4,10-triazatricyclo[7.4.0.0{circumflexover ( )}[3,7]]trideca-1,3(7),5,8-tetraen-10-yl]benzoate (90 mg, 0.14mmol, 1.00 equiv) in tetrahydrofuran/MeOH/H₂O (2/2/2 mL), sodiumhydroxide (23 mg, 0.57 mmol, 4.00 equiv). The resulting solution wasstiffed for overnight at 60 degree. The reaction mixture was cooled toroom temperature. The reaction was then quenched by the addition of 5 mLof water. The pH value of the solution was adjusted to 6 with hydrogenchloride (1 mol/L). The resulting solution was extracted with 2×10 mL ofethyl acetate and the organic layers combined. The resulting mixture waswashed with 3×10 mL of brine. The mixture was dried over anhydroussodium sulfate and concentrated under vacuum. The residue was appliedonto a silica gel column with ethyl acetate/petroleum ether (0:1-1:1).This resulted in 70 mg (80%) of4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[13-oxa-2,4,10-triazatricyclo[7.4.0.0{circumflexover ( )}[3,7]]trideca-1,3(7),5,8-tetraen-10-yl]benzoic acid as a yellowsolid.

LC-MS(ES, m/z): M+1=612, R,T=1.005 min. The measurements of theretention were done with a reversed phase column (C18). Shimadzu LCMS2020; 50*3.0 Kinetex 2.6u XB-C18, 2.6 microm; Eluent A: water (0.05%TFA); Eluent B: Acetonitrile; linear gradient.

Into a 8-mL round-bottom flask, was placed a solution of4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[13-oxa-2,4,10-triazatricyclo[7.4.0.0{circumflexover ( )}[3,7]]trideca-1,3(7),5,8-tetraen-10-yl]benzoic acid (35 mg,0.06 mmol, 1.00 equiv) in dichloromethane (5 mL),4-dimethylaminopyridine (27.8 mg, 0.23 mmol, 4.00 equiv),3-nitro-4-[(oxan-4-ylmethyl)amino]benzene-1-sulfonamide (21.7 mg, 0.07mmol, 1.20 equiv), EDCI (22 mg, 0.11 mmol, 2.00 equiv). The resultingsolution was stirred for overnight at room temperature. The resultingmixture was concentrated under vacuum. The crude product was purified byPrep-HPLC with the following conditions (Waters-2767): Column, X-bridgeRP18, 5 um, 19*100 mm; mobile phase, 0.03% ammonia in water (0.03%NH4HCO3 & NH4OH) and CH3CN (32% CH3CN up to 52% in 6 min); Detector, UV254 nm. This resulted in 28.3 mg (54%) of4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-N-([3-nitro-4-[(oxan-4-ylmethyl)amino]benzene]sulfonyl)-2-[13-oxa-2,4,10-triazatricyclo[7.4.0.0{circumflexover ( )}[3,7]]trideca-1,3(7),5,8-tetraen-10-yl]benzamide as a yellowsolid. LC-MS−: (ES, m/z): (ES, m/z): M+1=909, R.T=1.52 min. Themeasurements of the retention were done with a reversed phase column(C18). Shimadzu LCMS 2020; 50*3.0 Kinetex 2.6u XB-C18, 2.6 microm;Eluent A: water (0.05% TFA); Eluent B: Acetonitrile; linear gradient.H-NMR: (CDCl₃, 300 MHz) δ: 8.70 (s, 1H), 8.46 (m, 2H), 8.10-8.06 (m,1H), 7.89-7.60 (m, 1H), 7.10 (s, 1H), 6.94-6.71 (m, 5H), 6.49 (s, 1H),6.16 (s, 1H), 4.70-4.65 (m, 2H), 4.00-4.10 (m, 2H), 3.67-3.19 (m, 7H),3.20-3.00 (m, 4H), 2.78 (s, 1H), 2.58-2.52 (m, 2H), 2.27-2.17 (m, 3H),2.05-1.98 (m, 4H), 1.74-1.70 (m, 3H), 1.55-1.40 (m, 3H), 0.98 (s,6H).The measurements of the NMR spectra were done with BrukerAvanceIIIHD 300 MHz with a probe head of BBOF.

Example 3: Preparation of4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide

Into a 8-mL round-bottom flask, was placed a solution of4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[13-oxa-2,4,10-triazatricyclo[7.4.0.0{circumflexover ( )}[3,7]]trideca-1,3(7),5,8-tetraen-10-yl]benzoic acid (35 mg,0.06 mmol, 1.00 equiv) in dichloromethane (5 mL),4-dimethylaminopyridine (27.8 mg, 0.23 mmol, 4.00 equiv), EDCI (22 mg,0.11 mmol, 2.00 equiv),4-[(4-fluorooxan-4-yl)methyl]amino-3-nitrobenzene-1-sulfonamide (22.7mg, 0.07 mmol, 1.20 equiv). The resulting solution was stirred forovernight at room temperature. The resulting mixture was concentratedunder vacuum. The crude product was purified by Prep-HPLC with thefollowing conditions (Waters-2767): Column, X-bridge RP18, 5 um, 19*100mm; mobile phase, 0.03% ammonia in water (0.03% NH₄HCO₃ & NH₄OH) andCH₃CN (32% CH₃CN up to 52% in 6 min); Detector, UV 254 nm. This resultedin 26.2 mg (50%) of4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-N-[(4-[[(4-fluorooxan-4-yl)methyl]amino]-3-nitrobenzene)sulfonyl]-2-[13-oxa-2,4,10-triazatricyclo[7.4.0.0{circumflexover ( )}[3,7]]trideca-1,3(7),5,8-tetraen-10-yl]benzamide as a yellowsolid. LC-MS: (ES, m/z): (ES, m/z): M+1=927, R,T=1.27 min. Themeasurements of the retention were done with a reversed phase column(C18). Shimadzu LCMS 2020; 50*3.0 Kinetex 2.6u XB-C18, 2.6 microm;Eluent A: water (0.05% TFA); Eluent B: Acetonitrile; linear gradientfrom 5% acetonitrile to 100% acetonitrile in 3.5 minutes; Oventemperature 40° C.; flow:1.5 mL/min. H-NMR: (CDCl₃, 300 MHz) δ: 12.38(bs, 1H), 8.69 (d, J=2.1 Hz, 1H), 8.58 (t, J=6.3 Hz, 1H), 8.44 (s, 1H),8.07 (d, J=9.0 Hz, 1H), 7.90-7.87 (m, 1H), 7.24-7.22 (m, 2H), 7.08 (s,1H), 6.94 (m, 2H), 6.85 (s, 1H), 6.80-6.77 (m, 2H), 6.49 (s, 1H), 6.14(s, 1H), 4.74-4.67 (m, 2H), 3.91-3.80 (m, 2H), 3.80-3.44 (m, 6H), 3.17(m, 4H), 2.77 (s, 1H), 2.22-2.10 (m, 6H), 2.00 (s, 2H), 1.98-1.75 (m,3H), 1.80-1.60 (m, 2H), 1.55-1.40 (m, 2H), 0.94 (s, 6H). Themeasurements of the NMR spectra were done with BrukerAvanceIII HD 300MHz with a probe head of BBOF.

Example 4: Preparation of4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl-2,2,3,3-d4)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide

Synthesis of4-[[2-(trimethylsilyl)ethoxy]methyl](12,12-2H2)-13-oxa-2,4,10-triazatricyclo[7.4.0.0{circumflexover ( )}[3,7]]trideca-1(9),2,5,7-tetraen-11-one: Into a 8-mL vial, wasplaced4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazatricyclo[7.4.0.0{circumflexover ( )}[3,7]]trideca-1(9),2,5,7-tetraen-11-one (90 mg, 0.28 mmol, 1equiv), D20 (1 mL), MeOD (1 mL), Na₂CO₃ (89.6 mg, 0.85 mmol, 3.00equiv). The resulting solution was stirred for 48 h at 60° C. in an oilbath. The resulting solution was extracted with 3×3 mL ofdichloromethane. The organic layer was dried over anhydrous sodiumsulfate and concentrated under vacuum. This resulted in 60 mg (66%) of4-[[2-(trimethylsilyl)ethoxy]methyl](12,12-2H2)-13-oxa-2,4,10-triazatricyclo[7.4.0.0{circumflexover ( )}[3,7]]trideca-1(9),2,5,7-tetraen-11-one as a yellow solid.LC-MS-PH-PHNW-4-34-1: (ES, m/z): M+1=322,The measurements of theretention were done with a reversed phase column (C18). Shimadzu LCMS2020; 50*3.0 Kinetex 2.6u XB-C18, 2.6 microm; Eluent A: water (0.05%TFA); Eluent B: Acetonitrile; linear gradient from 5% acetonitrile to100% acetonitrile in 3.5 minutes; Oven temperature 40° C.; flow: 1.5mL/min. H-NMR-PH-PHNW-4-34-2: (d-DMSO, 300 ppm): 7.44-7.41 (m, 2H),6.43-6.42 (d, J=6 Hz, 1H), 5.46-5.41 (m, 2H), 3.51-3.46 (m, 2H), 1.24(s, 1H), 0.86-0.79 (m, 4H), −0.04-−0.05 (m, 9H).

Synthesis of4-[[2-(trimethylsilyl)ethoxy]methyl](11,11,12,12-2H4)-13-oxa-2,4,10-triazatricyclo[7.4.0.0{circumflexover ( )}[3,7]]trideca-1(9),2,5,7-tetraene: Into a 8-mL vial, was placed4-[[2-(trimethylsilyl)ethoxy]methyl](12,12-2H2)-13-oxa-2,4,10-triazatricyclo[7.4.0.0{circumflexover ( )}[3,7]]trideca-1(9),2,5,7-tetraen-11-one (60 mg, 0.19 mmol, 1equiv), THF (3 mL). This was followed by the addition of LiAlD₄ (31.3mg, 0.75 mmol, 3.99 equiv) in portions at 0° C. The resulting solutionwas stirred for overnight at room temperature. The reaction was thenquenched by the addition of 1 mL of D20. The resulting solution wasextracted with 3×5 mL of ethyl acetate. The organic layer was dried overanhydrous sodium sulfate and concentrated under vacuum. This resulted in25 mg (43.28%) of4-[[2-(trimethylsilyl)ethoxy]methyl](11,11,12,12-2H4)-13-oxa-2,4,10-triazatricyclo[7.4.0.0{circumflexover ( )}[3,7]]trideca-1(9),2,5,7-tetraene as a yellow solid.LC-MS-PH-PHNW-4-34-2: (ES, m/z): M+1=931. H-NMR-PH-PHNW-4-34-2: (CDCl₃,300 ppm): 7.35 (s, 1H), 7.17-7.15 (d, J=6 Hz, 1H), 6.35-6.34 (d, J=3 Hz,1H), 5.56-5.53 (m, 2H), 3.58-3.52 (m, 2H), 2.08 (s, 1H), 1.28 (s, 1H),0.93-0.88 (m, 3H), −0.04-−0.05 (m, 9H).

Synthesis of methyl4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-(4-[[2-(trimethylsilyl)ethoxy]methyl](11,11,12,12-2H4)-13-oxa-2,4,10-triazatricyclo[7.4.0.0{circumflexover ( )}[3,7]]trideca-1(9),2,5,7-tetraen-10-yl)benzoate: Into a 8-mLvial, was placed4-[[2-(trimethylsilyl)ethoxy]methyl](11,11,12,12-2H4)-13-oxa-2,4,10-triazatricyclo[7.4.0.0{circumflexover ( )}[3,7]]trideca-1(9),2,5,7-tetraene (25 mg, 0.08 mmol, 1 equiv),methyl2-bromo-4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)benzoate(55.9 mg, 0.11 mmol, 1.3 equiv), Dioxane (5 mL), Cs₂CO₃ (52.6 mg, 0.16mmol, 2 equiv),Chloro[9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene][2-amino-1,1-biphenyl-2-yl]palladium(II)(5 mg). The resulting solution was stirred for 2 h at 100° C. in an oilbath. After the reaction completed, the crude solution is concentratedand the residue was applied onto a silica gel column with ethylacetate/petroleum ether (0:1-1:1). This resulted in 20 mg (32.56%) ofmethyl4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-(4-[[2-(trimethylsilyl)ethoxy]methyl](11,11,12,12-2H4)-13-oxa-2,4,10-triazatricyclo[7.4.0.0{circumflexover ( )}[3,7]]trideca-1(9),2,5,7-tetraen-10-yl)benzoate as a yellowsolid. The measurements of the retention were done with a reversed phasecolumn (C18). Shimadzu LCMS 2020; 50*3.0 Kinetex 2.6u XB-C18, 2.6microm; Eluent A: water (0.05% TFA); Eluent B: Acetonitrile; lineargradient from 5% acetonitrile to 100% acetonitrile in 3.5 minutes; Oventemperature 40° C.; flow: 1.5 mL/min.

Synthesis of methyl4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[(11,11,12,12-2H4)-13-oxa-2,4,10-triazatricyclo[7.4.0.0{circumflexover ( )}[3,7]]trideca-1(9),2,5,7-tetraen-10-yl]benzoate. Into a 8-mLvial, was placed methyl4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-(4-[[2-(trimethylsilyl)ethoxy]methyl](11,11,12,12-2H4)-13-oxa-2,4,10-triazatricyclo[7.4.0.0{circumflexover ( )}[3,7]]trideca-1(9), (20 mg, 0.03 mmol, 1 equiv), THF (2 mL),TBAF (100 mg, 0.38 mmol, 14.54 equiv), ethane-1,2-diamine (1 mL, 0.02mmol, 0.63 equiv). The resulting solution was stirred for overnight at70° C. The resulting mixture was concentrated under vacuum. The residuewas applied onto a silica gel column with ethyl acetate/petroleum ether(0:1-1:1). This resulted in 12 mg (72.40%) of methyl4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[(11,11,12,12-2H4)-13-oxa-2,4,10-triazatricyclo[7.4.0.0{circumflexover ( )}[3,7]]trideca-1(9),2,5,7-tetraen-10-yl]benzoate as a yellowsolid. LC-MS-PH-PHNW-4-34-4: (ES, m/z): M+1=630. The measurements of theretention were done with a reversed phase column (C18). Shimadzu LCMS2020; 50*3.0 Kinetex 2.6u XB-C18, 2.6 microm; Eluent A: water (0.05%TFA); Eluent B: Acetonitrile; linear gradient from 5% acetonitrile to100% acetonitrile in 3.5 minutes; Oven temperature 40° C.; flow: 1.5mL/min.

Synthesis of4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[(11,11,12,12-2H4)-13-oxa-2,4,10-triazatricyclo[7.4.0.0{circumflexover ( )}[3,7]]trideca-1(9),2,5,7-tetraen-10-yl]benzoic acid: Into a8-mL vial, was placed methyl4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[(11,11,12,12-2H4)-13-oxa-2,4,10-triazatricyclo[7.4.0.0{circumflexover ( )}[3,7]]trideca-1(9),2,5,7-tetraen-10-yl]benzoate (12 mg, 0.02mmol, 1 equiv), MeOH (1 mL), H₂O (1 mL), THF (1 mL), NaOH (3.0 mg, 0.08mmol, 3.94 equiv). The resulting solution was stirred for overnight at60° C. in an oil bath. The pH value of the solution was adjusted to 5with HCl (1 mol/L). The reaction mixture was concentrated under vacuum.The residue was applied on a silica gel column and eluted withPE/EA(1:0-2:3). This resulted in 9 mg (76.71%) of4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[(11,11,12,12-2H4)-13-oxa-2,4,10-triazatricyclo[7.4.0.0{circumflexover ( )}[3,7]]trideca-1(9),2,5,7-tetraen-10-yl]benzoic acid as anoff-white solid. LC-MS-PH-PHNW-4-34-5: (ES, m/z): M+1=616. Themeasurements of the retention were done with a reversed phase column(C18). Shimadzu LCMS 2020; 50*3.0 Kinetex 2.6u XB-C18, 2.6 microm;Eluent A: water (0.05% TFA); Eluent B: Acetonitrile; linear gradientfrom 5% acetonitrile to 100% acetonitrile in 3.5 minutes; Oventemperature 40° C.; flow: 1.5 mL/min.

Synthesis of4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-N-(4-[[(4-fluorooxan-4-yl)methyl]amino]-3-nitrobenzenesulfonyl)-2-[(11,11,12,12-2H4)-13-oxa-2,4,10-triazatricyclo[7.4.0.0.0{circumflexover ( )}[3,7]]trideca-1(9),2,5,7-tetraen-10-yl]benzamide: Into a 8-mLvial, was placed4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[(11,11,12,12-2H4)-13-oxa-2,4,10-triazatricyclo[7.4.0.0{circumflexover ( )}[3,7]]trideca-1,3(7),5,8-tetraen-10-yl]benzoic acid (9 mg, 0.01mmol, 1 equiv),4-[[(4-fluorooxan-4-yl)methyl]amino]-3-nitrobenzene-1-sulfonamide (6.3mg, 0.02 mmol, 1.3 equiv), DCM (2 mL), DMAP (7.1 mg, 0.06 mmol, 3.98equiv), EDCI (5.6 mg, 0.03 mmol, 2 equiv). The resulting solution wasstirred for overnight at room temperature. The resulting mixture wasconcentrated under vacuum. The residue was applied onto a silica gelcolumn with dichloromethane/methanol (10:1). This resulted in 6 mg(44.10%) of4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-N-(4-[[(4-fluorooxan-4-yl)methyl]amino]-3-nitrobenzenesulfonyl)-2-[(11,11,12,12-2H4)-13-oxa-2,4,10-triazatricyclo[7.4.0.0.0{circumflexover ( )}[3,7]]trideca-1(9),2,5,7-tetraen-10-yl]benzamide as a yellowsolid. LC-MS-PH-PHNW-4-34-0: (ES, m/z): M+1=931. The measurements of theretention were done with a reversed phase column (C18). Shimadzu LCMS2020; 50*3.0 Kinetex 2.6u XB-C18, 2.6 microm; Eluent A: water (0.05%TFA); Eluent B: Acetonitrile; linear gradient from 5% acetonitrile to100% acetonitrile in 3.5 minutes; Oven temperature 40° C.; flow: 1.5mL/min. H-NMR-PH-PHNW-4-34-0: (d-DMSO, 300 ppm): 8.57 (s, 1H), 8.37 (s,1H), 7.58-7.55 (m, 1H), 7.37-7.35 (m, 3H), 7.08-7.05 (m, 3H), 6.87-6.76(m, 3H), 3.76-3.73 (m, 6H), 3.57-3.53 (m, 6H), 3.33 (m, 3H), 2.76-2.73(m, 2H), 2.26-2.20 (m, 6H), 1.98 (m, 2H), 1.81-1.76 (m, 5H), 1.41-1.39(m, 5H), 1.39 (m, 4H), 0.91-0.88 (m, 6H).

Example 5: Preparation of4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-(2-methyl-2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)benzamide

Synthesis of tert-butyl1-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-6-yloxy)propan-2-ylcarbamate.Into a 250 mL round-bottom flask was placed tert-butyl1-hydroxypropan-2-ylcarbamate (2.28 g, 13.05 mmol, 1.50 equiv), DMF (30mL), NaH (0.87 g, 21.75 mmol, 2.50 equiv) at 0° C. for 10 min.5-bromo-6-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine(3.0 g, 8.70 mmol, 1.00 equiv) was added. The resulting solution wasstirred overnight at room temperature. The resulting solution wasdiluted with 200 mL of H₂O. The resulting solution was extracted with3×300 mL of ethyl acetate and the organic layers combined. The resultingmixture was washed with 1×200 mL of H₂O and 1×200 mL sodiumchloride(aq). The resulting mixture was concentrated under vacuum. Theresidue was applied onto a silica gel column with PE/EA (5:1). Thisresulted in 2.2g (50%) of tert-butyl1-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-6-yloxy)propan-2-ylcarbamateas a yellow oil. LC-MS-PH-PHNW-4-35-1 (ES, m/z): LC-MS (M+1): 502;RT=1.50 min. The measurements of the retention were done with a reversedphase column (C18). Shimadzu LCMS 2020; 50*3.0 Kinetex 2.6u XB-C18, 2.6microm; Eluent A: water (0.05% TFA); Eluent B: Acetonitrile; lineargradient from 5% acetonitrile to 100% acetonitrile in 2.0 minutes; Oventemperature 40° C.; flow:1.5 mL/min.

Synthesis of tert-butyl2-methyl-6-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazine-1(6H)-carboxylate.Into a 100 mL round-bottom flask was placed tert-butyl1-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-6-yloxy)propan-2-ylcarbamate(2.2 g, 4.39 mmol, 1.00 equiv), dioxane (25 mL), Cs₂CO₃ (4.30 g, 13.17mmol, 3.00 equiv), X-phosPd 3G (1.04 g, 1.317 mmol, 0.30 equiv). Theresulting solution was stiffed overnight at 100° C. under N2. Theresulting mixture was concentrated under vacuum. The residue was appliedonto a silica gel column with PE/EA (3:1).This resulted in 1.26 g (68%)of tert-butyl2-methyl-6-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazine-1(6H)-carboxylateas a yellow oil. LC-MS-PH-PHNW-4-35-2 (ES, m/z): LC-MS (M+1): 420;RT=1.84 min. The measurements of the retention were done with a reversedphase column (C18). Shimadzu LCMS 2020; 50*3.0 Kinetex 2.6u XB-ODS, 2.6microm; Eluent A: water (0.05% TFA); Eluent B: Acetonitrile; lineargradient from 5% acetonitrile to 100% acetonitrile in 2.6 minutes; Oventemperature 40° C.; flow:1.0 mL/min.

Synthesis of2-methyl-6-((2-(trimethylsilyl)ethoxy)methyl)-1,2,3,6-tetrahydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazine: Into a 250 mL round-bottom flaskwas placed tert-butyl2-methyl-6-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazine-1(6H)-carboxylate(1.26 g, 3.00 mmol, 1.00 equiv), DCM (15 mL), ZnBr₂ (10.0 g, 30 mmol,10.0 equiv). The resulting solution was stirred at room temperature for3 h. The resulting solution was diluted with 50 mL of NaHCO₃. Theresulting solution was extracted with 3×50 mL of DCM and the organiclayers combined. The resulting mixture was washed with 1×50 mL of H₂Oand 1×50 mL sodium chloride(aq). The resulting mixture was concentratedunder vacuum. The residue was applied onto a silica gel column withPE/EA (1:1). This resulted in 800 mg (83%) of2-methyl-6-((2-(trimethylsilyl)ethoxy)methyl)-1,2,3,6-tetrahydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazineas a yellow oil. LC-MS-PH-PHNW-4-35-3 (ES, m/z): LC-MS (M+1): 320;RT=1.54 min. The measurements of the retention were done with a reversedphase column (C18). Shimadzu LCMS 2020; 50*3.0 Kinetex 2.6u XB-ODS, 2.6microm; Eluent A: water (0.05% TFA); Eluent B: Acetonitrile; lineargradient from 5% acetonitrile to 100% acetonitrile in 2.6 minutes; Oventemperature 40° C.; flow:1.0 mL/min.

Synthesis of methyl4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2-methyl-6-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)benzoate: Into a 100 mL round-bottomflask was placed tert-butyl1-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-6-yloxy)propan-2-ylcarbamate(300 mg, 0.94 mmol, 1.00 equiv), dioxane (15 mL), Cs₂CO₃ (920 mg, 2.82mmol, 3.00 equiv), XantphosPd 2G (83 mg, 0.094 mmol, 0.10 equiv), methyl2-bromo-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoate(1.0g, 1.88 mmol, 2.00equiv). The resulting solution was stirred overnightat 110° C. under N2. The resulting mixture was concentrated undervacuum. The residue was applied onto a silica gel column with PE/EA(5:1).This resulted in 360 mg (50%) of methyl4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2-methyl-6-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)benzoateas a yellow oil. LC-MS-PH-PHNW-4-35-4 (ES, m/z): LC-MS (M+1): 770;RT=1.56 min. The measurements of the retention were done with a reversedphase column (C18). Shimadzu LCMS 2020; 50*3.0 Kinetex 2.6u XB-ODS, 2.6microm; Eluent A: water (0.05% TFA); Eluent B: Acetonitrile; lineargradient from 5% acetonitrile to 100% acetonitrile in 2.6 minutes; Oventemperature 40° C.; flow:1.0 mL/min

Synthesis of methyl4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2-methyl-2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)benzoate Into a 100 mL round-bottom flask was placed tert-butyl methyl4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2-methyl-6-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)benzoate(300 mg, 0.39 mmol, 1.00 equiv), THF (10 mL), TBAF(3.0 g),ethane-1,2-diamine(5 mL). The resulting solution was stirred overnightat 60° C. The resulting mixture was concentrated under vacuum. Themixture was adjust PH<7 by 2N HCl. The resulting solution was extractedwith 3×200 mL of EA and the organic layers combined. The resultingmixture was washed with 1×10 mL of H₂O and 1×10 mL sodium chloride(aq).The resulting mixture was concentrated under vacuum. This resulted in120 mg (48%) of methyl4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2-methyl-2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)benzoateas a yellow oil. LC-MS-PH-PHNW-4-35-5 (ES, m/z): LC-MS (M+1): 640;RT=2.82 min. The measurements of the retention were done with a reversedphase column (C18). Shimadzu LCMS 2020; 50*3.0 Kinetex 2.6u HPH-C18, 2.6microm; Eluent A: water (0.05% NH₄HCO₃); Eluent B: Methanol; lineargradient from 10% acetonitrile to 98% acetonitrile in 3.5 minutes; Oventemperature 40° C.; flow: 0.8 mL/min

Synthesis of4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2-methyl-2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)benzoicacid. Into a 50 mL round-bottom flask was methyl4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2-methyl-2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)benzoate(70 mg, 0.11 mmol, 1.00 equiv), MeOH/H₂O (5/5 mL), NaOH (44 mg, 1.10mmol, 10 equiv).The resulting solution was stirred at 60° C. for 3h. Theresulting mixture was concentrated under vacuum. The residue was appliedonto a silica gel column with dichloromethane/methanol (10:1). Thisresulted in 50 mg (73%) of4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2-methyl-2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)benzoicacid as a white solid. LC-MS-PH-PHNW-4-35-6 (ES, m/z): LC-MS (M+1): 626;RT=2.45 min. The measurements of the retention were done with a reversedphase column (C18). Shimadzu LCMS 2020; 50*3.0 Kinetex 2.6u HPH-C18, 2.6microm; Eluent A: water (0.05% NH₄HCO₃); Eluent B: Methanol; lineargradient from 10% acetonitrile to 98% acetonitrile in 3.5 minutes; Oventemperature 40° C.; flow: 0.8 mL/min.

Synthesis of4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methy1)piperazin-1-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-(2-methyl-2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)benzamide:Into a 50-mL 1-necked round-bottom flask was placed4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2-methyl-2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)benzoicacid (40 mg, 0.064 mol, 1.00 equiv), DCM (4 mL), EDCI (49 mg, 0.256mmol, 4.00 equiv), DMAP (16 mg, 0.128 mmol, 2.00 equiv),4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrobenzenesulfonamide(28mg, 0.0832 mol, 1.30 equiv). The resulting solution was stirredovernight at 40° C. The resulting mixture was concentrated under vacuum.This resulted in 2.9 mg (70%) of4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-(2-methyl-2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)benzamideas a yellow solid. LC-MS-PH-PHNW-4-35-OA(ES, m/z): LC-MS (M+1):941;RT=5.02 min. The measurements of the retention were done with a reversedphase column (C18). Shimadzu LCMS 2020; 50*3.0 Kinetex 2.6u AscentisExpress C18, 2.6 microm; Eluent A: water (0.05% TFA); Eluent B:Methanol; linear gradient from 5% acetonitrile to 95% acetonitrile in7.0 minutes; Oven temperature 40° C.; flow: 1.0 mL/min.

Example 6: Preparation of(S)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-(3-methyl-2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)benzamideand(R)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-(3-methyl-2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)benzamide

Synthesis of12-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazatricyclo[7.4.0.0{circumflexover ( )}[3,7]]trideca-1(9),2,5,7-tetraen-11-one: Into a 100-mLround-bottom flask, was placed5-amino-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridin-6-ol(1.5 g, 5.37 mmol, 1 equiv), DMF (50 mL), K₂CO₃ (2.2 g, 16.11 mmol, 3equiv). This was followed by the addition of 2-chloropropanoyl chloride(1.4 g, 10.74 mmol, 2 equiv) dropwise with stirring at 0° C. Theresulting solution was stirred for overnight at room temperature. Thereaction was then quenched by the addition of 50 mL of water. Theresulting solution was extracted with 2×50 mL of ethyl acetate. Theresulting mixture was washed with 2×50 mL of brine. The mixture wasdried over anhydrous sodium sulfate and filtrate and concentrated undervacuum. The residue was applied onto a silica gel column with ethylacetate/petroleum ether (0:1-1:3). This resulted in 500 mg (27.93%) of12-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazatricyclo[7.4.0.0{circumflexover ( )}[3,7]]trideca-1(9),2,5,7-tetraen-11-one as a yellow solid.LC-MS-PH-PHNW-4-37-1: (ES, m/z): M+1=334, R,T=1.123 min. Themeasurements of the retention were done with a reversed phase column(C18). Shimadzu LCMS 2020; 50*3.0 Kinetex 2.6u XB-C18, 2.6 microm;Eluent A: water (0.05% TFA); Eluent B: Acetonitrile; linear gradientfrom 5% acetonitrile to 100% acetonitrile in 3.5 minutes; Oventemperature 40° C.; flow: 1.5 mL/min. H-NMR-PH-PHNW-4-37-1: (CDCl₃, 300ppm): 8.34 (s, 1H), 7.63 (d, J=3 Hz, 1H), 7.42-7.28 (m, 1H), 6.46 (d,J=3 Hz, 1H), 5.68 (s, 2H), 4.92-4.85 (m, 1H), 3.63-3.53 (m, 2H),1.85-1.81 (d, J=12 Hz, 3H), 0.94-0.89 (m, 2H), −0.154 (s, 9H). Themeasurements of the NMR spectra were done with BrukerAvanceIII HD 300MHz with a probe head of BBOF.

Synthesis of12-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazatricyclo[7.4.0.0{circumflexover ( )}[3,7]]trideca-1(9),2,5,7-tetraene & (12R orS)-12-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazatricyclo[7.4.0.0{circumflexover ( )}[3,7]]trideca-1(9),2,5,7-tetraene (Assumed) & (12S orR)-12-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazatricyclo[7.4.0.0{circumflexover ( )}[3,7]]trideca-1(9),2,5,7-tetraene(Assumed): Into a 100-mL3-necked round-bottom flask, was placed12-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazatricyclo[7.4.0.0{circumflexover ( )}[3,7]]trideca-1(9),2,5,7-tetraen-11-one (500 mg, 1.50 mmol, 1equiv), THF (20 mL). This was followed by the addition of LiAlH₄ (113.8mg, 3.00 mmol, 2 equiv), in portions at 0° C. The resulting solution wasstirred for 1 overnight at room temperature. The reaction was thenquenched by the addition of 20 mL of water. The solids were filteredout. The resulting solution was extracted with 2×20 mL of ethyl acetate.The resulting mixture was washed with 2×20 mL of brine. The mixture wasdried over anhydrous sodium sulfate and filtrate and concentrated undervacuum. The residue was applied onto a silica gel column with ethylacetate/petroleum ether (0:1-1:3). This resulted in 450 mg (93%) of12-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazatricyclo[7.4.0.0{circumflexover ( )}[3,7]]trideca-1(9),2,5,7-tetraene as a yellow solid.

The crude12-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazatricyclo[7.4.0.0{circumflexover ( )}[3,7]]trideca-1(9),2,5,7-tetraene (450 mg) was purified byChiral-Prep-HPLC with the following conditions: (SHIMADZU LC-20AT):Column, CHIRALPAK IC; mobile phase A: n-hexane, Phase B: ethanol;Detector, 220 nm. This resulted in 200 mg (44%) of (12R orS)-12-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazatricyclo[7.4.0.0{circumflexover ( )}[3,7]]trideca-1(9),2,5,7-tetraene as a yellow solid(Assumed).

This resulted in 200 mg (44%) of (12S orR)-12-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazatricyclo[7.4.0.0{circumflexover ( )}[3,7]]trideca-1(9),2,5,7-tetraene as a yellow solid(Assumed).

LC-MS-PH-PHNW-4-37-2: (ES, m/z): M+1=320, R,T=1.107 min.

The measurements of the retention were done with a reversed phase column(C18). Shimadzu LCMS 2020; 50*3.0 Kinetex 2.6u XB-C18, 2.6 microm;Eluent A: water (0.05% TFA); Eluent B: Acetonitrile; linear gradientfrom 5% acetonitrile to 100% acetonitrile in 3.5 minutes; Oventemperature 40° C.; flow: 1.5 mL/min.

H-NMR-PH-PHNW-4-37-2: (CDCl3, 300 ppm): 7.63 (s, 1H), 7.17 (s, 1H),6.36-6.35 (d, J=3 Hz, 1H), 5.57-5.52 (m, 2H), 4.59-4.55 (m, 1H),3.62-3.46 (m, 3H), 3.18-3.14 (m, 1H), 1.62-1.44 (m, 3H), 0.93-0.88 (m,2H), −0.17 (s, 9H).

Synthesis of methyl4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[(12RorS)-12-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazatricyclo[7.4.0.0{circumflexover ( )}[3,7]]trideca-1(9),2,4,10-triazatricyclo[7.4.0.0{circumflexover ( )}3,7]trideca-1(9),2,5,7-tetraen-10-yl]benzoate(Assumed): Into a8-mL vial, was placed(12R)-12-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazatricyclo[7.4.0.0{circumflexover ( )}[3,7]]trideca-1(9),2,5,7-tetraene (200 mg, 0.63 mmol, 1 equiv),methyl2-bromo-4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)benzoate(399.6 mg, 0.75 mmol, 1.2 equiv), Cs₂CO₃ (611.9 mg, 1.88 mmol, 3 equiv),Dioxane (5 mL),Chloro[9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene][2-amino-1,1-biphenyl-2-yl]palladium(II)(120 mg). The resulting solution was stirred for 2 hr at 110° C. in anoil bath. The resulting mixture was concentrated under vacuum. Theresidue was applied onto a silica gel column with ethylacetate/petroleum ether (0:1-1:10). This resulted in 250 mg (51.83%) ofmethyl4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[(12RorS)-12-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazatricyclo[7.4.0.0{circumflexover ( )}[3,7]]trideca-1(9),2,4,10-triazatricyclo[7.4.0.0{circumflexover ( )}3,7]trideca-1(9),2,5,7-tetraen-10-yl]benzoate as a yellowsolid(Assumed).

Synthesis of methyl4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[(12Ror S)-12-methyl-13-oxa-2,4,10-triazatricyclo[7.4.0.0{circumflex over( )}[3,7]]trideca-1(9),2,5,7-tetraen-10-yl]benzoate(Assumed) Into a100-mL round-bottom flask, was placed methyl4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[(12RorS)-12-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazatricyclo[7.4.0.0{circumflexover ( )}[3,7]]trideca-1(9),2 (250 mg, 0.32 mmol, 1 equiv), TBAF (3 g,11.47 mmol, 35.36 equiv), THF (30 mL), ethane-1,2-diamine (2 g, 33.28mmol, 102.56 equiv). The resulting solution was stirred for 12 h at 70°C. in an oil bath. The reaction was then quenched by the addition of 50mL of water. The resulting solution was extracted with 2×50 mL of ethylacetate. The resulting mixture was washed with 3×50 mL of brine. Themixture was dried over anhydrous sodium sulfate and filtrate andconcentrated under vacuum. The residue was applied onto a silica gelcolumn with ethyl acetate/petroleum ether (0:1-1:3). This resulted in 90mg (43%) of methyl4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[(12Ror S)-12-methyl-13-oxa-2,4,10-triazatricyclo[7.4.0.0{circumflex over( )}[3,7]]trideca-1(9),2,5,7-tetraen-10-yl]benzoate as a yellowsolid(Assumed). H-NMR-PH-PHNW-4-37-50: (CDCl3, 300 ppm): 8.24 (s, 1H),7.89-7.86 (d, J=9 Hz, 1H), 7.32-7.24 (m, 6H), 7.14-7.01 (m, 1H),6.97-6.94 (m, 2H), 6.73-6.65 (m, 2H), 6.18 (s, 1H), 3.67-3.53 (m, 3H),3.32-3.18 (m, 3H), 2.98-2.80 (m, 1H), 2.30-2.04 (m, 6H), 1.99 (s, 2H),1.56-1.50 (m, 5H), 0.91-0.88 (m, 6H).

Synthesis of4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[(12Ror S)-12-methyl-13-oxa-2,4,10-triazatricyclo[7.4.0.0{circumflex over( )}[3,7]]trideca-1(9),2,5,7-tetraen-10-yl]benzoic acid(Assumed). Into a8-mL vial, was placed methyl4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[(12Ror S)-12-methyl-13-oxa-2,4,10-triazatricyclo[7.4.0.0{circumflex over( )}[3,7]]trideca-1(9),2,5,7-tetraen-10-yl]benzoate (90 mg, 0.14 mmol, 1equiv), MeOH (1 mL), H₂O (1 mL), THF (1 mL), NaOH (22.5 mg, 0.56 mmol, 4equiv). The resulting solution was stirred for overnight at 60° C. in anoil bath. The pH value of the solution was adjusted to 5 with HCl (1mol/L). The resulting mixture was concentrated under vacuum. The residuewas applied onto a silica gel column with dichloromethane/methanol(1:0-10:1). This resulted in 80 mg (90%) of4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[(12Ror S)-12-methyl-13-oxa-2,4,10-triazatricyclo[7.4.0.0{circumflex over( )}[3,7]]trideca-1(9),2,5,7-tetraen-10-yl]benzoic acid as a yellowsolid(Assumed). LC-MS-PH-PHNW-4-37-60: (ES, m/z): M+1=626, R,T=1.035min. The measurements of the retention were done with a reversed phasecolumn (C18). Shimadzu LCMS 2020; 50*3.0 Kinetex 2.6u XB-C18, 2.6microm; Eluent A: water (0.05% TFA); Eluent B: Acetonitrile; lineargradient from 5% acetonitrile to 100% acetonitrile in 3.5 minutes; Oventemperature 40° C.; flow: 1.5 mL/min.

Synthesis of4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-N-(4-[[(4-fluorooxan-4-yl)methyl]amino]-3-nitrobenzenesulfonyl)-2-[(12Ror S)-12-methyl-13-oxa-2,4,10-triazatricyclo[7.4.0.0{circumflex over( )}[3,7]]trideca-1(9),2,5,7-tetraen-10-yl]benzamide(Assumed): Into a8-mL vial, was placed4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[(12Ror S)-12-methyl-13-oxa-2,4,10-triazatricyclo[7.4.0.0{circumflex over( )}[3,7]]trideca-1(9),2,5,7-tetraen-10-yl]benzoic acid (90 mg, 0.14mmol, 1 equiv),4-[[(4-fluorooxan-4-yl)methyl]amino]-3-nitrobenzene-1-sulfonamide (57.5mg, 0.17 mmol, 1.2 equiv), DCM (5 mL), DMAP (70.2 mg, 0.57 mmol, 4equiv), EDCI (55.1 mg, 0.29 mmol, 2.00 equiv). The resulting solutionwas stirred for overnight at room temperature. The resulting mixture wasconcentrated. The crude product was purified by Flash-Prep-HPLC with thefollowing conditions (IntelFlash-1): Column, C18 silica gel; mobilephase, Water(0.1% FA) and ACN (48.0% ACN up to 53.0% in 7 min, hold95.0% in 1 min, down to 48.0% in 1 min, hold 48.0% in 1 min) within 5min; Detector, UV 254 nm. This resulted in 28 mg (20%) of4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-N-(4-[[(4-fluorooxan-4-yl)methyl]amino]-3-nitrobenzenesulfonyl)-2-[(12Ror S)-12-methyl-13-oxa-2,4,10-triazatricyclo[7.4.0.0{circumflex over( )}[3,7]]trideca-1(9),2,5,7-tetraen-10-yl]benzamide as a yellow solid(Assumed). 19.8 mg product was submitted (Assumed).LC-MS-PH-PHNW-4-37-0: (ES, m/z): M+1=941, R,T=3.04 min. The measurementsof the retention were done with a reversed phase column (C18). ShimadzuLCMS 2020; 50*3.0 Kinetex 2.6u XB-C18, 2.6 microm; Eluent A: water(0.05% TFA); Eluent B: Acetonitrile; linear gradient from 5%acetonitrile to 100% acetonitrile in 3.5 minutes; Oven temperature 40°C.; flow: 1.5 mL/min. H-NMR-PH-PHNW-4-37-0: (d-DMSO, 300 ppm): 8.59 (s,1H), 8.54 (s, 1H), 7.55-7.53 (m, 1H), 7.36-7.29 (d, J=6 Hz, 3H),7.12-7.06 (m, 3H), 6.80-6.72 (m, 3H), 5.95 (m, 1H), 4.53-4.51 (m, 1H),3.78-3.43 (m, 7H), 3.21-3.00 (m, 5H), 2.22-2.17 (m, 5H), 1.96-1.75 (m,6H), 1.58-1.56 (m, 5H), 0.93-0.88 (m, 6H).

Synthesis of methyl4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[(12SorR)-12-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazatricyclo[7.4.0.0{circumflexover ( )}[3,7]]trideca-1(9),2,2,5,7-tetraen-10-yl]benzoate(Assumed):Into a 8-mL vial, was placed (12S orR)-12-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazatricyclo[7.4.0.0{circumflexover ( )}[3,7]]trideca-1(9),2,5,7-tetraene (200 mg, 0.63 mmol, 1 equiv),methyl2-bromo-4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)benzoate(399.6 mg, 0.75 mmol, 1.2 equiv), Cs₂CO₃ (611.9 mg, 1.88 mmol, 3 equiv),Dioxane (5 mL),Chloro[9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene][2-amino-1,1-biphenyl-2-yl]palladium(II)(120 mg). The resulting solution was stirred for 2 h at 110° C. in anoil bath. The resulting mixture was concentrated under vacuum. Theresidue was applied onto a silica gel column with ethylacetate/petroleum ether (0:1-1:10). This resulted in 250 mg (51%) ofmethyl4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[(12SorR)-12-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazatricyclo[7.4.0.0{circumflexover ( )}[3,7]]trideca-1(9),2,2,5,7-tetraen-10-yl]benzoate as a yellowsolid(Assumed).

Synthesis of methyl4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[(12Sor R)-12-methyl-13-oxa-2,4,10-triazatricyclo[7.4.0.0{circumflex over( )}[3,7]]trideca-1(9),2,5,7-tetraen-10-yl]benzoate (Assumed): into a100-mL round-bottom flask, was placed methyl4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[(12SorR)-12-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazatricyclo[7.4.0.0{circumflexover ( )}[3,7]]trideca-1(9),2 (250 mg, 0.32 mmol, 1 equiv), TBAF (3 g,11.47 mmol, 35.36 equiv), THF (30 mL), ethane-1,2-diamine (2 g, 33.28mmol, 102.56 equiv). The resulting solution was stirred for 12 h at 70°C. in an oil bath. The reaction was then quenched by the addition of 50mL of water. The resulting solution was extracted with 2×50 mL of ethylacetate. The resulting mixture was washed with 3×50 mL of brine. Themixture was dried over anhydrous sodium sulfate and filtrate andconcentrated under vacuum. The residue was applied onto a silica gelcolumn with ethyl acetate/petroleum ether (0:1-1:3). This resulted in 90mg (43%) of methyl4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[(12Sor R)-12-methyl-13-oxa-2,4,10-triazatricyclo[7.4.0.0{circumflex over( )}[3,7]]trideca-1(9),2,5,7-tetraen-10-yl]benzoate as a yellowsolid(Assumed).

LC-MS-PH-PHNW-4-38-50: (ES, m/z): M+1=640, R,T=1.424 min. Themeasurements of the retention were done with a reversed phase column(C18). Shimadzu LCMS 2020; 50*3.0 Kinetex 2.6u XB-C18, 2.6 microm;Eluent A: water (0.05% TFA); Eluent B: Acetonitrile; linear gradientfrom 5% acetonitrile to 100% acetonitrile in 3.5 minutes; Oventemperature 40° C.; flow: 1.5 mL/min. H-NMR-PH-PHNW-4-38-50: (CDCl3, 300ppm): 8.24 (s, 1H), 7.89-7.86 (d, J=9 Hz, 1H), 7.32-7.24 (m, 6H),7.14-7.01 (m, 1H), 6.97-6.94 (m, 2H), 6.73-6.65 (m, 2H), 6.18 (s, 1H),3.67-3.53 (m, 3H), 3.32-3.18 (m, 3H), 2.98-2.80 (m, 1H), 2.30-2.04 (m,6H), 1.99 (s, 2H), 1.56-1.50 (m, 5H), 0.91-0.88 (m, 6H).

Synthesis of4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[(12Sor R)-12-methyl-13-oxa-2,4,10-triazatricyclo[7.4.0.0{circumflex over( )}[3,7]]trideca-1(9),2,5,7-tetraen-10-yl]benzoic acid (Assumed): Intoa 8-mL vial, was placed methyl4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[(12Sor R)-12-methyl-13-oxa-2,4,10-triazatricyclo[7.4.0.0{circumflex over( )}[3,7]]trideca-1(9),2,5,7-tetraen-10-yl]benzoate (90 mg, 0.14 mmol, 1equiv), MeOH (1 mL), H₂O (1 mL), THF (1 mL), NaOH (22.5 mg, 0.56 mmol,4.00 equiv). The resulting solution was stiffed for overnight at 60° C.in an oil bath. The pH value of the solution was adjusted to 5 with HCl(1 mol/L). The resulting mixture was concentrated under vacuum. Theresidue was applied onto a silica gel column with chloroform/methanol(1:0-10:1). This resulted in 80 mg (90%) of4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[(12Sor R)-12-methyl-13-oxa-2,4,10-triazatricyclo[7.4.0.0{circumflex over( )}[3,7]]trideca-1(9),2,5,7-tetraen-10-yl]benzoic acid as asolid(Assumed): LC-MS-PH-PHNW-4-38-60: (ES, m/z): M+1=626, R,T=1.039min. The measurements of the retention were done with a reversed phasecolumn (C18). Shimadzu LCMS 2020; 50*3.0 Kinetex 2.6u XB-C18, 2.6microm; Eluent A: water (0.05% TFA); Eluent B: Acetonitrile; lineargradient from 5% acetonitrile to 100% acetonitrile in 3.5 minutes; Oventemperature 40° C.; flow: 1.5 mL/min.

Synthesis of4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-N-(4-[[(4-fluorooxan-4-yl)methyl]amino]-3-nitrobenzenesulfonyl)-2-[(12Sor R)-12-methyl-13-oxa-2,4,10-triazatricyclo[7.4.0.0{circumflex over( )}[3,7]]trideca-1(9),2,5,7-tetraen-10-yl]benzamide(Assumed): Into a8-mL vial, was placed4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[(12Sor R)-12-methyl-13-oxa-2,4,10-triazatricyclo[7.4.0.0{circumflex over( )}[3,7]]trideca-1(9),2,5,7-tetraen-10-yl]benzoic acid (90 mg, 0.14mmol, 1 equiv),4-[[(4-fluorooxan-4-yl)methyl]amino]-3-nitrobenzene-1-sulfonamide (57.5mg, 0.17 mmol, 1.2 equiv), DCM (5 mL), DMAP (70.2 mg, 0.57 mmol, 4equiv), EDCI (55.1 mg, 0.29 mmol, 2 equiv). The resulting solution wasstirred for overnight at room temperature. The resulting mixture wasconcentrated. The crude product was purified by Flash-Prep-HPLC with thefollowing conditions (IntelFlash-1): Column, C18 silica gel; mobilephase, Water (0.1% FA) and ACN (48.0% ACN up to 53.0% in 7 min, hold95.0% in 1 min, down to 48.0% in 1 min, hold 48.0% in 1 min) within 5min; Detector, UV 254 nm. This resulted in 26 mg (19%) of4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-N-(4-[[(4-fluorooxan-4-yl)methyl]amino]-3-nitrobenzenesulfonyl)-2-[(12Sor R)-12-methyl-13-oxa-2,4,10-triazatricyclo[7.4.0.0{circumflex over( )}[3,7]]trideca-1(9),2,5,7-tetraen-10-yl]benzamide as a yellow solid.19.6 mg product was submitted(Assumed). LC-MS-PH-PHNW-4-38-0: (ES, m/z):M+1=941, R,T=3.036 min. The measurements of the retention were done witha reversed phase column (C18). Shimadzu LCMS 2020; 50*3.0 Kinetex 2.6uXB-C18, 2.6 microm; Eluent A: water (0.05% TFA); Eluent B: Acetonitrile;linear gradient from 5% acetonitrile to 100% acetonitrile in 3.5minutes; Oven temperature 40° C.; flow: 1.5 mL/min.H-NMR-PH-PHNW-4-38-0: (d-DMSO, 300 ppm): 8.56 (s, 1H), 8.36 (s, 1H),7.62-7.54 (m, 1H), 7.37-7.30 (m, 3H), 7.14-7.04 (m, 3H), 6.98-6.92 (m,3H), 5.94 (m, 1H), 4.53 (m, 1H), 3.79-3.71 (m, 4H), 3.65-3.54 (m, 3H),3.44 (m, 4H), 2.78-2.73 (m, 2H), 2.23-2.18 (m, 6H), 1.97-1.91 (m, 2H),1.87-1.81 (m, 4H), 1.50-1.20 (m, 5H), 0.91-0.88 (m, 6H).

Example 7: Preparation of4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,3-dimethyl-2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide

Synthesis of12,12-dimethyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazatricyclo[7.4.0.0{circumflexover ( )}[3,7]]trideca-1,3(7),5,8-tetraen-11-one: Into a 100-mLround-bottom flask, was placed5-amino-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridin-6-ol(1 g, 3.58 mmol, 1 equiv), CH₃CN (20 mL), methyl2-bromo-2-methylpropanoate (647.9 mg, 3.58 mmol, 1.0 equiv), Cs₂CO₃ (1.7g, 5.37 mmol, 1.5 equiv). The resulting solution was stirred for 2 h at80° C. in an oil bath. The resulting mixture was concentrated undervacuum. The residue was applied onto a silica gel column with ethylacetate/petroleum ether (1:3). This resulted in 270 mg (21%) of12,12-dimethyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazatricyclo[7.4.0.0{circumflexover ( )}[3,7]]trideca-1,3(7),5,8-tetraen-11-one as a light yellowsolid. LC-MS-PH-PHNW-4-40-2: (ES, m/z): M+1=348, R,T=1.164 min. Themeasurements of the retention were done with a reversed phase column(C18). Shimadzu LCMS 2020; 50*3.0 Kinetex 2.6u XB-C18, 2.6 microm;Eluent A: water (0.05% TFA); Eluent B: Acetonitrile; linear gradientfrom 5% acetonitrile to 100% acetonitrile in 3.5 minutes; Oventemperature 40° C.; flow: 1.5 mL/min.

Synthesis of12,12-dimethyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazatricyclo[7.4.0.0{circumflexover ( )}[3,7]]trideca-1,3(7),5,8-tetraene: Into a 8-mL vial, was placed12,12-dimethyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazatricyclo[7.4.0.0{circumflexover ( )}[3,7]]trideca-1,3(7),5,8-tetraen-11-one (250 mg, 0.72 mmol, 1equiv), THF (3 mL). This was followed by the addition of LiAlH₄ (54.6mg, 1.44 mmol, 2 equiv), in portions at 0° C. The resulting solution wasstirred for overnight at room temperature. The reaction was thenquenched by the addition of 5 mL of water. The solids were filtered out.The resulting solution was extracted with 2×10 mL of ethyl acetate. Theorganic layer was dried over anhydrous sodium sulfate and concentratedunder vacuum. The residue was applied onto a silica gel column withethyl acetate/petroleum ether (0:1-1:5). This resulted in 140 mg (58%)of12,12-dimethyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazatricyclo[7.4.0.0{circumflexover ( )}[3,7]]trideca-1,3(7),5,8-tetraene as a yellow solid.

Synthesis of4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-(12,12-dimethyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazatricyclo[7.4.0.0{circumflexover ( )}[3,7]]trideca-1,3(7), 5,8-tetraen-10-yl)benzoate: Into a 8-mLvial, was placed12,12-dimethyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazatricyclo[7.4.0.0{circumflexover ( )}[3,7]]trideca-1,3(7),5,8-tetraene (140 mg, 0.42 mmol, 1 equiv),methyl2-bromo-4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)benzoate(267.9 mg, 0.50 mmol, 1.2 equiv), Cs₂CO₃ (410.3 mg, 1.26 mmol, 3 equiv),Dioxane (2 mL),Chloro[9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene][2-amino-1,1-biphenyl-2-yl]palladium(II)(80 mg). The resulting solution was stirred for 2 h at 110° C. in an oilbath. The resulting mixture was concentrated under vacuum. The residuewas applied onto a silica gel column with ethyl acetate/petroleum ether(0:1-1:3). This resulted in 130 mg (39%) of methyl4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-(12,12-dimethyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazatricyclo[7.4.0.0{circumflexover ( )}[3,7]]trideca-1,3(7), 5,8-tetraen-10-yl)benzoate as a yellowsolid. LC-MS-PH-PHNW-4-40-4: (ES, m/z): M+1=784, R,T=1.331 min. Themeasurements of the retention were done with a reversed phase column(C18). Shimadzu LCMS 2020; 50*3.0 Kinetex 2.6u XB-C18, 2.6 microm;Eluent A: water (0.05% TFA); Eluent B: Acetonitrile; linear gradientfrom 5% acetonitrile to 100% acetonitrile in 3.5 minutes; Oventemperature 40° C.; flow: 1.5 mL/min.

Synthesis of methyl4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[12,12-dimethyl-13-oxa-2,4,10-triazatricyclo[7.4.0.0{circumflexover ( )}[3,7]]trideca-1,3(7),5,8-tetraen-10-yl]benzoate: Into a 40-mLvial, was placed methyl4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-(12,12-dimethyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazatricyclo[7.4.0.0{circumflexover ( )}[3,7]]trideca-1,3(7), (130 mg, 0.17 mmol, 1 equiv), TBAF (3 g),THF (10 mL), ethane-1,2-diamine (2 g). The resulting solution wasstirred for overnight at 60° C. in an oil bath. The reaction was thenquenched by the addition of 10 mL of water. The resulting solution wasextracted with 2×10 mL of ethyl acetate. The resulting mixture waswashed with 3×10 mL of brine. The mixture was dried over anhydroussodium sulfate and filtrate and concentrated under vacuum. The residuewas applied onto a silica gel column with ethyl acetate/petroleum ether(0:1-1:3). This resulted in 110 mg (crude) of methyl4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[12,12-dimethyl-13-oxa-2,4,10-triazatricyclo[7.4.0.0{circumflexover ( )}[3,7]]trideca-1,3(7),5,8-tetraen-10-yl]benzoate as a yellowsolid. LC-MS-PH-PHNW-4-40-5: (ES, m/z): M+1=654, R,T=1.107 min. Themeasurements of the retention were done with a reversed phase column(C18). Shimadzu LCMS 2020; 50*3.0 Kinetex 2.6u XB-C18, 2.6 microm;Eluent A: water (0.05% TFA); Eluent B: Acetonitrile; linear gradientfrom 5% acetonitrile to 100% acetonitrile in 3.5 minutes; Oventemperature 40° C.; flow: 1.5 mL/min.

Synthesis of4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[12,12-dimethyl-13-oxa-2,4,10-triazatricyclo[7.4.0.0{circumflexover ( )}[3,7]]trideca-1,3(7),5,8-tetraen-10-yl]benzoic acid: Into a8-mL vial, was placed methyl4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[12,12-dimethyl-13-oxa-2,4,10-triazatricyclo[7.4.0.0{circumflexover ( )}[3,7]]trideca-1,3(7),5,8-tetraen-10-yl]benzoate (80 mg, 0.12mmol, 1 equiv), MeOH (1 mL), THF (1 mL), H₂O (1 mL), NaOH (19.6 mg, 0.49mmol, 4 equiv). The resulting solution was stirred for overnight at 60°C. in an oil bath. The pH value of the solution was adjusted to 5 withHCl (1 mol/L). The resulting mixture was concentrated under vacuum. Theresidue was applied onto a silica gel column withdichloromethane/methanol (1:0-10:1). This resulted in 60 mg (76.64%) of4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[12,12-dimethyl-13-oxa-2,4,10-triazatricyclo[7.4.0.0{circumflexover ( )}[3,7]]trideca-1,3(7),5,8-tetraen-10-yl]benzoic acid as a yellowsolid. LC-MS-PH-PHNW-4-40-6: (ES, m/z): M+1=640, R,T=1.359 min. Themeasurements of the retention were done with a reversed phase column(C18). Shimadzu LCMS 2020; 50*3.0 Kinetex 2.6u XB-C18, 2.6 microm;Eluent A: water (0.05% TFA); Eluent B: Acetonitrile; linear gradientfrom 5% acetonitrile to 100% acetonitrile in 3.5 minutes; Oventemperature 40° C.; flow: 1.5 mL/min.

Synthesis of4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[12,12-dimethyl-13-oxa-2,4,10-triazatricyclo[7.4.0.0{circumflexover( )}[3,7]]trideca-1(9),2,5,7-tetraen-10-yl]-N-(4-[[(4-fluorooxan-4-yl)methyl]amino]-3-nitrobenzenesulfonyl)benzamide:Into a 8-mL vial, was placed4-[[(4-fluorooxan-4-yl)methyl]amino]-3-nitrobenzene-1-sulfonamide (37.5mg, 0.11 mmol, 1.2 equiv), DCM (5 mL),4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[12,12-dimethyl-13-oxa-2,4,10-triazatricyclo[7.4.0.0{circumflexover ( )}[3,7]]trideca-1,3(7),5,8-tetraen-10-yl]benzoic acid (60 mg,0.09 mmol, 1 equiv), EDCI (35.9 mg, 0.19 mmol, 2 equiv), DMAP (45.8 mg,0.37 mmol, 4 equiv). The resulting solution was stirred for overnight atroom temperature. The resulting mixture was concentrated under vacuum.The crude product was purified by Flash-Prep-HPLC with the followingconditions (IntelFlash-1): Column, C18 silica gel; mobile phase,Water(0.1% FA) and ACN (48.0% ACN up to 53.0% in 7 min, hold 95.0% in 1min, down to 48.0% in 1 min within 5; Detector, UV 254 nm. This resultedin 25 mg (27%) of4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[12,12-dimethyl-13-oxa-2,4,10-triazatricyclo[7.4.0.0{circumflexover( )}[3,7]]trideca-1(9),2,5,7-tetraen-10-yl]-N-(4-[[(4-fluorooxan-4-yl)methyl]amino]-3-nitrobenzenesulfonyl)benzamideas a yellow solid. 20.6 mg product was submitted. LC-MS-PH-PHNW-4-40-0:(ES, m/z): M+1=955, R,T=2.655 min. The measurements of the retentionwere done with a reversed phase column (C18). Shimadzu LCMS 2020; 50*3.0Kinetex 2.6u XB-C18, 2.6 microm; Eluent A: water (0.05% TFA); Eluent B:Acetonitrile; linear gradient from 5% acetonitrile to 100% acetonitrilein 3.5 minutes; Oven temperature 40° C.; flow: 1.5 mL/min.H-NMR-PH-PHNW-4-40-0: (d-DMSO, 300 ppm): 8.56 (s, 1H), 8.36 (s, 1H),7.56-7.49 (m, 2H), 7.36-7.33 (m, 2H), 7.06-7.00 (m, 3H), 6.93-6.90 (m,1H), 6.88-6.74 (M, 2H), 5.99 (m, 1H), 3.78-3.74 (m, 4H), 3.67-3.50 (m,2H), 3.23 (m, 4H), 2.76-2.72 (m, 2H), 2.22-2.16 (m, 6H), 1.96-1.75 (m,6H), 1.41-1.39 (m, 8H), 0.91-0.88 (m, 6H).

Example 8: Preparation of4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-3-yl)methyl)amino)phenyl)sulfonyl)benzamide

Synthesis of3-nitro-4-(((tetrahydro-2H-pyran-3-yl)methyl)amino)benzenesulfonamide:Into a 50-mL round-bottom flask, was placed(tetrahydro-2H-pyran-3-yl)methanamine (200 mg, 1.74 mmol, 1.00 equiv),THF (5 mL), 4-fluoro-3-nitrobenzene-1-sulfonamide (383 mg, 1.74 mmol,1.00 equiv), Cs₂CO₃ (1.134 g, 3.48 mmol, 2.00 equiv). The resultingsolution was stirred for 3h at 50 degrees C. in an oil bath. Theresulting mixture was concentrated under vacuum. The residue was appliedonto a silica gel column with ethyl acetate/petroleum ether (1/1). Thisresulted in 270 mg (49.3%) of3-nitro-4-(((tetrahydro-2H-pyran-3-yl)methyl)amino) benzenesulfonamideas a yellow solid. LC-MS-PH-PHNW-4-41-1: (ES, m/z): M+1=316, R,T=1.25min. The measurements of the retention were done with a reversed phasecolumn (C18). Shimadzu LCMS 2020; 50*3.0 Kinetex 2.6u XB-ODS, 2.6microm; Eluent A: water (0.5% FA); Eluent B: Acetonitrile(0.05% TFA);linear gradient from 5% acetonitrile to 100% acetonitrile in 2.6minutes; Oven temperature 40° C.; flow:1.0 mL/min.

Synthesis of4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-3-yl)methyl)amino)phenyl)sulfonyl)benzamide:Into a 100-mL round-bottom flask, was placed4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[13-oxa-2,4,10-triazatricyclo[7.4.0.0{circumflexover ( )}[3,7]]trideca-1,3(7),5,8-tetraen-10-yl]benzoic acid (50 mg,0.082 mmol, 1.00 equiv) in dichloromethane (5 mL), EDCI (63 mg, 0.328mmol, 4.00 equiv), 4-dimethylaminopyridine (20 mg, 0.164 mmol, 2.00equiv),3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide(26 mg, 0.082 mmol, 1.00 equiv). The resulting solution was stirred forovernight at 40° C. The resulting mixture was concentrated under vacuum.The crude product was purified by Prep-HPLC with the followingconditions (Waters-2767): Column, X-bridge RP18, 5 um, 19*100 mm; mobilephase, 0.03% ammonia in water (0.03% NH₄HCO₃ & NH₄OH) and CH₃CN (32%CH₃CN up to 52% in 6 min); Detector, UV 254 nm. This resulted in 12.8 mg(17%) of4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamideas a yellow solid. LC-MS-PH-PHNW-4-41-0: (ES, m/z): M+1=909, R,T=1.60min. The measurements of the retention were done with a reversed phasecolumn (C18). Shimadzu LCMS 2020; 50*3.0 Kinetex 2.6u XB-C18, 2.6microm; Eluent A: water (0.05% TFA); Eluent B: Acetonitrile; lineargradient from 5% acetonitrile to 100% acetonitrile in 3.0 minutes; Oventemperature 40° C.; flow: 1.5 mL/min. 1H NMR (300 MHz, Chloroform-d) δ12.40 (s, 1H), 8.72 (s, 1H), 8.63 (s, 1H), 8.44 (t, J=5.5 Hz, 1H), 8.10(d, J=9.0 Hz, 1H), 7.93-7.82 (m, 1H), 7.25 (s, 4H), 7.13 (t, J=2.9 Hz,1H), 7.00-6.68 (m, 6H), 6.52 (s, 1H), 6.17 (d, J=3.3 Hz, 1H), 4.71 (dd,J=23.6, 10.7 Hz, 2H), 3.99-3.79 (m, 3H), 3.70 (s, 1H), 3.57 (dd, J=18.5,10.9 Hz, 3H), 3.46-3.17 (m, 7H), 2.80 (s, 2H), 2.29 (s, 3H), 2.21 (s,2H), 2.03 (d, J=12.3 Hz, 5H), 1.75-1.60 (m, 4H), 1.44 (d, J=8.7 Hz, 3H),1.28 (s, 1H), 0.97 (s, 6H), 0.87 (s, 1H). The measurements of the NMRspectra were done with BrukerAvanceIII HD 300 MHz with a probe head ofBBOF.

Example 9: Preparation of(S)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3-methyl-2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide

Synthesis of6-(tert-butoxy)-N-(diphenylmethylidene)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridin-5-amine:Into a 250-mL round-bottom flask, was placed a solution of5-bromo-6-fluoro-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridine(20.7 g, 60 mmol, 1.00 equiv) in dioxane (300 mL), t-BuOK (20.5 g, 180mmol, 3.00 equiv), xantphos (6.9 g, 12 mmol, 0.20 equiv),Pd₂(dba)₃.CHCl₃ (5.7 g, 0.10 equiv), diphenylmethanimine (14.04 g, 78mmol, 1.20 equiv). The resulting solution was stirred for overnight at100° C. The resulting mixture was concentrated under vacuum. The residuewas applied onto a silica gel column with ethyl acetate/petroleum ether(0:1-1:20). This resulted in 15 g (crude) of6-(tert-butoxy)-N-(diphenylmethylidene)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridin-5-amineas white oil. LC-MS-PH-PHNW-4-7-9: (ES, m/z): M+1=500.

Synthesis of5-amino-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridin-6-olhydrogen chloride salt: Into a 500-mL round-bottom flask, was placed6-(tert-butoxy)-N-(diphenylmethylidene)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridin-5-amine(15 g, 30.02 mmol, 1.00 equiv) in dioxane (120 mL), HCl/dioxane(4M, 30mL). The resulting solution was stirred for 5 h at room temperature. Theresulting solution was diluted with 500 mL of ether. The solids werecollected by filtration. This resulted in 5 g (crude) of5-amino-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridin-6-olhydrogen chloride salt as a red solid, Q-NMR show it might convertedinto 3 hydrogen chloride salt. LC-MS-PH-PHNW-4-10-1: (ES, m/z): M+1=280,R,T=0.811 min. The measurements of the retention were done with areversed phase column (C18). Shimadzu LCMS 2020; 50*3.0 Kinetex 2.6uXB-C18, 2.6 microm; Eluent A: water (0.05% TFA); Eluent B: Acetonitrile;linear gradient.

Synthesis of12-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazatricyclo[7.4.0.0{circumflexover ( )}[3,7]]trideca-1(9),2,5,7-tetraen-11-one: Into a 100-mLround-bottom flask, was placed5-amino-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridin-6-ol(1.5 g, 5.37 mmol, 1 equiv), DMF (50 mL), K₂CO₃ (2.2 g, 16.11 mmol, 3equiv). This was followed by the addition of 2-chloropropanoyl chloride(1.4 g, 10.74 mmol, 2 equiv) dropwise with stirring at 0° C. Theresulting solution was stirred for overnight at room temperature. Thereaction was then quenched by the addition of 50 mL of water. Theresulting solution was extracted with 2×50 mL of ethyl acetate. Theresulting mixture was washed with 2×50 mL of brine. The mixture wasdried over anhydrous sodium sulfate and filtrate and concentrated undervacuum. The residue was applied onto a silica gel column with ethylacetate/petroleum ether (0:1-1:3). This resulted in 500 mg (27.93%) of12-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazatricyclo[7.4.0.0{circumflexover ( )}[3,7]]trideca-1(9),2,5,7-tetraen-11-one as a yellow solid.LC-MS-PH-PHNW-4-37-1: (ES, m/z): M+1=334, R,T=1.123 min. Themeasurements of the retention were done with a reversed phase column(C18). Shimadzu LCMS 2020; 50*3.0 Kinetex 2.6u XB-C18, 2.6 microm;Eluent A: water (0.05% TFA); Eluent B: Acetonitrile; linear gradientfrom 5% acetonitrile to 100% acetonitrile in 3.5 minutes; Oventemperature 40° C.; flow: 1.5 mL/min. H-NMR-PH-PHNW-4-37-1: (CDCl3, 300ppm): 8.34 (s, 1H), 7.63 (d, J=3 Hz, 1H), 7.42-7.28 (m, 1H), 6.46 (d,J=3 Hz, 1H), 5.68 (s, 2H), 4.92-4.85 (m, 1H), 3.63-3.53 (m, 2H),1.85-1.81 (d, J=12 Hz, 3H), 0.94-0.89 (m, 2H), −0.154 (s, 9H).

Synthesis of12-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazatricyclo[7.4.0.0{circumflexover ( )}[3,7]]trideca-1(9),2,5,7-tetraene & (12S)-12-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazatricyclo[7.4.0.0{circumflexover ( )}[3,7]]trideca-1(9),2,5,7-tetraene & (12R)-12-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazatricyclo[7.4.0.0{circumflexover ( )}[3,7]]trideca-1(9),2,5,7-tetraene: Into a 100-mL 3-neckedround-bottom flask, was placed12-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazatricyclo[7.4.0.0{circumflexover ( )}[3,7]]trideca-1(9),2,5,7-tetraen-11-one (500 mg, 1.50 mmol, 1equiv), THF (20 mL). This was followed by the addition of LiAlH₄ (113.8mg, 3.00 mmol, 2 equiv), in portions at 0° C. The resulting solution wasstirred for 1 overnight at room temperature. The reaction was thenquenched by the addition of 20 mL of water. The solids were filteredout. The resulting solution was extracted with 2×20 mL of ethyl acetate.The resulting mixture was washed with 2×20 mL of brine. The mixture wasdried over anhydrous sodium sulfate and filtrate and concentrated undervacuum. The residue was applied onto a silica gel column with ethylacetate/petroleum ether (0:1-1:3). This resulted in 450 mg (93%) of12-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazatricyclo[7.4.0.0{circumflexover ( )}[3,7]]trideca-1(9),2,5,7-tetraene as a yellow solid.

The crude12-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazatricyclo[7.4.0.0{circumflexover ( )}[3,7]]trideca-1(9),2,5,7-tetraene (450 mg) was purified byChiral-Prep-HPLC with the following conditions: (SHIMADZU LC-20AT):Column, CHIRALPAK IC; mobile phase A: n-hexane, Phase B: ethanol;Detector, 220 nm. This resulted in 200 mg (44%) of(12S)-12-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazatricyclo[7.4.0.0{circumflexover ( )}[3,7]]trideca-1(9),2,5,7-tetraene as a yellow solid.

This resulted in 200 mg (44%) of(12R)-12-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazatricyclo[7.4.0.0{circumflexover ( )}[3,7]]trideca-1(9),2,5,7-tetraene as a yellow solid.LC-MS-PH-PHNW-4-37-2: (ES, m/z): M+1=320, R,T=1.107 min.

The measurements of the retention were done with a reversed phase column(C18). Shimadzu LCMS 2020; 50*3.0 Kinetex 2.6u XB-C18, 2.6 microm;Eluent A: water (0.05% TFA); Eluent B: Acetonitrile; linear gradientfrom 5% acetonitrile to 100% acetonitrile in 3.5 minutes; Oventemperature 40° C.; flow: 1.5 mL/min. H-NMR-PH-PHNW-4-37-2: (CDCl3, 300ppm): 7.63 (s, 1H), 7.17 (s, 1H), 6.36-6.35 (d, J=3 Hz, 1H), 5.57-5.52(m, 2H), 4.59-4.55 (m, 1H), 3.62-3.46 (m, 3H), 3.18-3.14 (m, 1H),1.62-1.44 (m, 3H), 0.93-0.88 (m, 2H), −0.17 (s, 9H).

Synthesis of methyl4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[(12S)-12-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazatricyclo[7.4.0.0{circumflexover ( )}[3,7]]trideca-1(9),2,4,10-triazatricyclo[7.4.0.0{circumflexover ( )}3,7]trideca-1(9),2,5,7-tetraen-10-yl]benzoate: Into a 8-mLvial, was placed(12S)-12-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazatricyclo[7.4.0.0{circumflexover ( )}[3,7]]trideca-1(9),2,5,7-tetraene (200 mg, 0.63 mmol, 1 equiv),methyl2-bromo-4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)benzoate(399.6 mg, 0.75 mmol, 1.2 equiv), Cs₂CO₃ (611.9 mg, 1.88 mmol, 3 equiv),Dioxane (5 mL),Chloro[9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene][2-amino-1,1-biphenyl-2-yl]palladium(II)(120 mg). The resulting solution was stirred for 2 hr at 110° C. in anoil bath. The resulting mixture was concentrated under vacuum. Theresidue was applied onto a silica gel column with ethylacetate/petroleum ether (0:1-1:10). This resulted in 250 mg (51.83%) ofmethyl4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[(12S)-12-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazatricyclo[7.4.0.0{circumflexover ( )}[3,7]]trideca-1(9),2,4,10-triazatricyclo[7.4.0.0{circumflexover ( )}3,7]trideca-1(9),2,5,7-tetraen-10-yl]benzoate as a yellowsolid.

Synthesis of methyl4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[(12S)-12-methyl-13-oxa-2,4,10-triazatricyclo[7.4.0.0{circumflexover ( )}[3,7]]trideca-1(9),2,5,7-tetraen-10-yl]benzoate. Into a 100-mLround-bottom flask, was placed methyl4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[(12S)-12-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazatricyclo[7.4.0.0{circumflexover ( )}[3,7]]trideca-1(9),2 (250 mg, 0.32 mmol, 1 equiv), TBAF (3 g,11.47 mmol, 35.36 equiv), THF (30 mL), ethane-1,2-diamine (2 g, 33.28mmol, 102.56 equiv). The resulting solution was stirred for 12 h at 70°C. in an oil bath. The reaction was then quenched by the addition of 50mL of water. The resulting solution was extracted with 2×50 mL of ethylacetate. The resulting mixture was washed with 3×50 mL of brine. Themixture was dried over anhydrous sodium sulfate and filtrate andconcentrated under vacuum. The residue was applied onto a silica gelcolumn with ethyl acetate/petroleum ether (0:1-1:3). This resulted in 90mg (43%) of methyl4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[(12S)-12-methyl-13-oxa-2,4,10-triazatricyclo[7.4.0.0{circumflexover ( )}[3,7]]trideca-1(9),2,5,7-tetraen-10-yl]benzoate as a yellowsolid. H-NMR-PH-PHNW-4-37-50: (CDCl3, 300 ppm): 8.24 (s, 1H), 7.89-7.86(d, J=9 Hz, 1H), 7.32-7.24 (m, 6H), 7.14-7.01 (m, 1H), 6.97-6.94 (m,2H), 6.73-6.65 (m, 2H), 6.18 (s, 1H), 3.67-3.53 (m, 3H), 3.32-3.18 (m,3H), 2.98-2.80 (m, 1H), 2.30-2.04 (m, 6H), 1.99 (s, 2H), 1.56-1.50 (m,5H), 0.91-0.88 (m, 6H).

Synthesis of4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[(12S)-12-methyl-13-oxa-2,4,10-triazatricyclo[7.4.0.0{circumflex over( )}[3,7]]trideca-1(9),2,5,7-tetraen-10-yl]benzoic acid. Into a 8-mLvial, was placed methyl4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[(12S)-12-methyl-3-oxa-2,4,10-triazatricyclo[7.4.0.0{circumflexover ( )}[3,7]]trideca-1(9),2,5,7-tetraen-10-yl]benzoate (90 mg, 0.14mmol, 1 equiv), MeOH (1 mL), H₂O (1 mL), THF (1 mL), NaOH (22.5 mg, 0.56mmol, 4 equiv). The resulting solution was stirred for overnight at 60°C. in an oil bath. The pH value of the solution was adjusted to 5 withHCl (1 mol/L). The resulting mixture was concentrated under vacuum. Theresidue was applied onto a silica gel column withdichloromethane/methanol (1:0-10:1). This resulted in 80 mg (90%) of4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[(12S)-12-methyl-13-oxa-2,4,10-triazatricyclo[7.4.0.0{circumflexover ( )}[3,7]]trideca-1(9),2,5,7-tetraen-10-yl]benzoic acid as a yellowsolid. LC-MS: (ES, m/z): M+1=626, R,T=1.035 min. The measurements of theretention were done with a reversed phase column (C18). Shimadzu LCMS2020; 50*3.0 Kinetex 2.6u XB-C18, 2.6 microm; Eluent A: water (0.05%TFA); Eluent B: Acetonitrile; linear gradient from 5% acetonitrile to100% acetonitrile in 3.5 minutes; Oven temperature 40° C.; flow: 1.5mL/min.

Synthesis of(S)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3-methyl-2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide.Into a 8-mL vial, was placed4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[(12Ror S)-12-methyl-13-oxa-2,4,10-triazatricyclo[7.4.0.0{circumflex over( )}[3,7]]trideca-1(9),2,5,7-tetraen-10-yl]benzoic acid (90 mg, 0.14mmol, 1 equiv),4-[[(4-fluorooxan-4-yl)methyl]amino]-3-nitrobenzene-1-sulfonamide (57.5mg, 0.17 mmol, 1.2 equiv), DCM (5 mL), DMAP (70.2 mg, 0.57 mmol, 4equiv), EDCI (55.1 mg, 0.29 mmol, 2.00 equiv). The resulting solutionwas stirred for overnight at room temperature. The resulting mixture wasconcentrated. The crude product was purified by Flash-Prep-HPLC with thefollowing conditions (IntelFlash-1): Column, C18 silica gel; mobilephase, Water(0.1% FA) and ACN (48.0% ACN up to 53.0% in 7 min, hold95.0% in 1 min, down to 48.0% in 1 min, hold 48.0% in 1 min) within 5min; Detector, UV 254 nm. This resulted in 22 mg (20%) of(S)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3-methyl-2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide.LC-MS: (ES, m/z): M+1=923, R,T=2.653 min. The measurements of theretention were done with a reversed phase column (C18). Shimadzu LCMS2020; 50*3.0 Kinetex 2.6u XB-C18, 2.6 microm; Eluent A: water (0.05%TFA); Eluent B: Acetonitrile; linear gradient from 5% acetonitrile to100% acetonitrile in 3.5 minutes; Oven temperature 40° C.; flow: 1.5mL/min. H-NMR: (d-CDCl₃, 300 ppm): 8.62 (s, 1H), 8.44-8.42 (m, 2H),8.09-8.06 (m, 1H), 7.85-7.70 (m, 1H), 7.28-7.22 (m, 2H), 6.94-6.80 (m,3H), 6.72-6.62 (m, 2H), 6.10 (s, 1H), 4.05-4.00 (m, 2H), 3.50-3.17 (m,10H), 2.95-2.35 (m, 2H), 2.27-2.19 (m, 4H), 1.98-1.70 (m, 5H), 1.60-1.26(m, 11H), 0.95 (s, 6H).

Example 10: Preparation of(R)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3-methyl-2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide

Synthesis of N-[(2R)-2-hydroxypropyl]-4-methylbenzene-1-sulfonamide:Into a 250-mL round-bottom flask, was placed (2R)-1-aminopropan-2-ol (5g, 1 equiv), DCM (70 mL), TsCl (12.67 g, 1 equiv). This was followed bythe addition of TEA (7.41 g, 1.1 equiv) at 0° C. The resulting solutionwas stirred for 3 hr at 0° C. The resulting mixture was concentrated.The residue was applied onto a silica gel column with ethylacetate/petroleum ether (1/1). This resulted in 8 g ofN-(2R)-2-hydroxypropyl]-4-methylbenzene-1-sulfonamide as a white solid.¹H NMR ((300 MHz, DMSO-d6, ppm): δ 7.74-7.63 (m, 2H), 7.52-7.34 (m, 3H),4.66 (d, J=4.7 Hz, 1H), 3.58 (qd, J=6.3, 4.8 Hz, 1H), 2.73-2.50 (m, 2H),2.39 (s, 3H), 0.99 (d, J=6.2 Hz, 3H).

Synthesis of methyl2-bromo-4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)benzoate:Into a 250-mL round-bottom flask, was placed a solution of1-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazine(15.09 g, 47.32 mmol, 1.00 equiv) in DMA (150 mL), DIEA (12.9 g, 99.81mmol, 2.00 equiv), methyl 2-bromo-4-fluorobenzoate (11.6 g, 49.78 mmol,1.00 equiv). The resulting solution was stirred for 12 h at 100 degree.The reaction mixture was cooled to room temperature. The reaction wasthen quenched by the addition of 50 mL of water. The resulting solutionwas extracted with 3×100 mL of ethyl acetate and the organic layerscombined. The resulting mixture was washed with 3×100 mL of brine. Themixture was dried over anhydrous sodium sulfate, then filtered andconcentrated under vacuum. The residue was applied onto a silica gelcolumn with ethyl acetate/petroleum ether (0:1-1:5). This resulted in 7g (crude) of methyl2-bromo-4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)benzoateas yellow oil. LC-MS: (ES, m/z): M+1=533, 531.

Synthesis ofN-[(2R)-2-[(5-bromo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridin-6-yl)oxy]propyl]-4-methylbenzene-1-sulfonamide:Into a 100-mL round-bottom flask, was placedN-[(2R)-2-hydroxypropyl]-4-methylbenzene-1-sulfonamide (1 g, 1.5 equiv),DMF (3 mL). This was followed by the addition of NaH (0.35 g, 3 equiv)at 0° C. in 10 min. To this was added5-bromo-6-fluoro-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridine(1 g, 1 equiv) at 0° C. The resulting solution was stirred for 4 hr atroom temperature. The reaction was then quenched by the addition of 20mL of water. The resulting solution was extracted with 3×50 mL of ethylacetate and the organic layers combined and concentrated. The residuewas applied onto a silica gel column with ethyl acetate/petroleum ether(1/3). This resulted in 400 mg ofN-[(2R)-2-[(5-bromo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridin-6-yl)oxy]propyl]-4-methylbenzene-1-sulfonamideas a yellow solid. ¹H-NMR (300 MHz, DMSO-d6, ppm): δ 8.18 (s, 1H),7.72-7.62 (m, 2H), 7.41 (d, J=3.5 Hz, 1H), 7.28 (d, J=8.0 Hz, 2H), 6.42(d, J=3.6 Hz, 1H), 5.50 (q, J=10.8 Hz, 2H), 5.16 (q, J=6.1 Hz, 1H),3.53-3.38 (m, 2H), 3.13 (dd, J=13.4, 6.0 Hz, 1H), 2.98 (dd, J=13.4, 5.8Hz, 1H), 2.29 (s, 3H), 1.28 (d, J=6.2 Hz, 3H), 0.80 (ddt, J=16.1, 14.1,7.1 Hz, 2H), 0.13 (s, 9H).

Synthesis of(12R)-12-methyl-10-(4-methylbenzenesulfonyl)-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazatricyclo[7.4.0.0{circumflexover ( )}[3,7]]trideca-1(9),2,5,7-tetraene: Into a 100-mL round-bottomflask purged and maintained with an inert atmosphere of nitrogen, wasplacedN-[(2R)-2-[(5-bromo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridin-6-yl)oxy]propyl]-4-methylbenzene-1-sulfonamide(3.9 g, 1 equiv), dioxane (50 mL), t-BuXPhos 3G (560 mg, 0.1 equiv),Cs₂O₃ (6.9 g, 3 equiv). The resulting solution was stirred for 4 hr at90° C. The resulting mixture was concentrated. The residue was appliedonto a silica gel column with ethyl acetate/petroleum ether (1/3). Thisresulted in 3.3 g of(12R)-12-methyl-10-(4-methylbenzenesulfonyl)-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazatricyclo[7.4.0.0{circumflexover ( )}[3,7]]trideca-1(9),2,5,7-tetraene as colorless oil. ¹H-NMR (300MHz, DMSO-d6, ppm): δ 8.28 (s, 1H), 7.56-7.39 (m, 3H), 7.39-7.30 (m,2H), 6.52 (d, J=3.6 Hz, 1H), 5.43 (s, 2H), 4.28 (dd, J=14.6, 2.6 Hz,1H), 3.61-3.41 (m, 3H), 3.26-3.11 (m, 1H), 2.35 (s, 3H), 1.32-1.11 (m,3H), 0.89-0.74 (m, 2H), 0.11 (s, 9H).

Synthesis of(12R)-12-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazatricyclo[7.4.0.0{circumflexover ( )}[3,7]]trideca-1(9),2,5,7-tetraene: Into a 100-mL 3-neckedround-bottom flask, was placed Na (1.3 1 g, 9.4 equiv), naphthalene(0.76 g, 6 equiv). This was followed by the addition of DME (15 mL) for30 min at room temperature. To this was added the solution(12R)-12-methyl-10-(4-methylbenzenesulfonyl)-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazatricyclo[7.4.0.0{circumflexover ( )}[3,7]]trideca-1(9),2,5,7-tetraene (2.8 g, 1 equiv) in THF (15mL) at −78° C. The resulting solution was stirred for 3 hr at roomtemperature. The reaction was then quenched by the addition of 30 mL ofNH₄C1. The resulting solution was extracted with 3×100 mL of ethylacetate and the organic layers combined and concentrated. The residuewas applied onto a silica gel column with ethyl acetate/petroleum ether(1/3). This resulted in 1.4 g of(12R)-12-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazatricyclo[7.4.0.0{circumflexover ( )}[3,7]]trideca-1(9),2,5,7-tetraene as a colorless oil. LC-MS(ES, m/z): 320 [M+1]⁺; RT=1.61 min.

Synthesis of methyl4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[(12S)-12-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazatricyclo[7.4.0.0{circumflexover ( )}[3,7]]trideca-1(9),2,5,7-tetraen-10-yl]benzoate: Into a 250-mLround-bottom flask purged and maintained with an inert atmosphere ofnitrogen, was placed(12R)-12-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazatricyclo[7.4.0.0{circumflexover ( )}[3,7]]trideca-1(9),2,5,7-tetraene (1.178 g, 1 equiv), methyl2-bromo-4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)benzoate(2.35 g, 1.2 equiv), dioxane (15 mg, 15 equiv), Cs₂CO₃ (3.62 g, 3equiv), XantPhos (328 mg, 0.1 equiv). The resulting solution was stiffedfor 2 hr at 110° C. The resulting mixture was concentrated. The residuewas applied onto a silica gel column with ethyl acetate/petroleum ether(1/3). This resulted in 3.2 g of methyl4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[(12S)-12-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazatricyclo[7.4.0.0{circumflexover ( )}[3,7]]trideca-1(9),2,5,7-tetraen-10-yl]benzoate as a yellowsolid. LC-MS (ES, m/z): 770 [M+1]⁺; RT=1.33 min.

Synthesis of methyl4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[(12R)-12-methyl-13-oxa-2,4,10-triazatricyclo[7.4.0.0{circumflexover ( )}[3,7]]trideca-1(9),2,5,7-tetraen-10-yl]benzoate: Into a 250-mLround-bottom flask, was placed methyl4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[(12R)-12-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazatricyclo[7.4.0.0{circumflexover ( )}[3,7]]trideca-1(9),2,5,7-tetraen-10-yl]benzoate (3.2 g, 1equiv), THF (50 mL), TBAF (20 g), ethane-1,2-diamine (33 g). Theresulting solution was stirred for 5 hr at 70° C. The reaction was thenquenched by the addition of 50 mL of water. The resulting solution wasextracted with 3×100 mL of ethyl acetate and the organic layers combinedand concentrated. The residue was applied onto a silica gel column withdichloromethane/methanol (10/1). This resulted in 2.2 g of methyl4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[(12R)-12-methyl-13-oxa-2,4,10-triazatricyclo[7.4.0.0{circumflexover ( )}[3,7]]trideca-1(9),2,5,7-tetraen-10-yl]benzoate as a yellowsolid. LC-MS− (ES, m/z): 640 [M+1]*; RT=2.51 min

Synthesis of4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[(12R)-12-methyl-13-oxa-2,4,10-triazatricyclo[7.4.0.0{circumflexover ( )}[3,7]]trideca-1(9),2,5,7-tetraen-10-yl]benzoic acid: Into a250-mL round-bottom flask, was placed methyl4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[(12R)-12-methyl-13-oxa-2,4,10-triazatricyclo[7.4.0.0{circumflexover ( )}[3,7]]trideca-1(9),2,5,7-tetraen-10-yl]benzoate (2.2 g, 1equiv), MEOH/H₂O/THF (10 mL/10 ml/10 mL). The resulting solution wasstiffed for 5 hr at 60° C. The resulting mixture was concentrated. Theresulting solution was extracted with 3×100 mL of dichloromethane andthe organic layers combined and concentrated. The residue was appliedonto a silica gel column with dichloromethane/methanol (10/1). Thisresulted in 1.6 g of4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[(12R)-12-methyl-13-oxa-2,4,10-triazatricyclo[7.4.0.0{circumflexover ( )}[3,7]]trideca-1(9),2,5,7-tetraen-10-yl]benzoic acid as yellowoil. LC-MS (ES, m/z): 626 [M+1]*; RT=2.47 min Synthesis of(R)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3-methyl-2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide:Into a 250-mL round-bottom flask, was placed4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[(12R)-12-methyl-13-oxa-2,4,10-triazatricyclo[7.4.0.0{circumflexover ( )}[3,7]]trideca-1(9),2,5,7-tetraen-10-yl]benzoic acid (1.6 g, 1equiv), DCM (20 mL),3-nitro-4-[[(oxan-4-yl)methyl]amino]benzene-1-sulfonamide (890 mg, 1.2equiv), DMAP (1.25 g, 4 equiv), EDCI (980 mg, 2 equiv). The resultingsolution was stirred for 14 hr at room temperature. The resultingmixture was concentrated. The residue was applied onto a silica gelcolumn with EA/DCM (1/10). This resulted in 0.82 g of(R)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3-methyl-2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamideas a yellow solid. LC-MS (ES, m/z): 923 [M+1]; RT=3.50 min. [a]=+17.8(C=0.105 g/100 mL in CH₂Cl₂, T=27.0° C.) ¹H NMR (300 MHz, CDCl₃, PPM): δ12.48 (s, 1H), 8.62 (d, J=2.4 Hz, 2H), 8.54-8.38 (m, 1H), 8.16-7.95 (m,1H), 7.81-7.71 (m, 1H), 7.32-7.12 (m, 6H), 7.07 (t, J=2.9 Hz, 1H),6.97-6.77 (m, 3H), 6.76-6.60 (m, 2H), 6.52 (s, 1H), 6.09 (d, J=3.0 Hz,1H), 4.88 (d, J=7.7 Hz, 1H), 4.02 (dd, J=11.8, 4.2 Hz, 2H), 3.55-3.34(m, 4H), 3.32-3.14 (m, 5H), 3.08 (s, 1H), 2.77 (d, J=9.6 Hz, 2H), 2.28(s, 3H), 2.19 (s, 2H), 1.99 (d, J=7.6 Hz, 4H), 1.72 (d, J=12.7 Hz, 2H),1.45 (ddd, J=24.5, 12.3, 5.8 Hz, 6H), 0.94 (d, J=2.1 Hz, 6H).

The compounds below were/are being prepared by methods substantiallyidentical, similar, or analogous to those disclosed in above Schemes andExamples:

Example Chemical Name m/z(MH⁺) Cpd-1 (R)-4-(4-((4′-chloro-5,5-dimethyl-977 3,4,5,6-tetrahydro-[1,1′- biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4- (((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)- 2-(3-(trifluoromethyl)-2,3-dihydropyrrolo[3′,2′:5,6] pyrido[2,3-b][l,4]oxazin-1(6H)-yl)benzamide Cpd-2 (S)-4-(4-((4′-chloro-5,5-dimethyl- 9773,4,5,6-tetrahydro-[1,1′- biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2-(3-(trifluoromethyl)-2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][l,4]oxazin-1(6H)-yl)benzamide Cpd-34-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′- 925biphenyl]-2-yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]thiazin-1(6H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide Cpd-4(R)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6- 993tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2-(3-(trifluoromethyl)-2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][l,4]thiazin- 1(6H)-yl)benzamide Cpd-5(S)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro- 993[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2-(3-(trifluoromethyl)-2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]thiazin-1(6H)-yl)benzamide Cpd-64-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′- 957biphenyl]-2-yl)methyl)piperazin-l-yl)-2-(4,4-dioxido-2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][l,4]thiazin-1(6H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide Cpd-7N-((4-((((R)-l,4-dioxan-2-yl)methyl)amino)-3- 925nitrophenyl)sulfonyl)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-((S)-3-methyl-2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)benzamide Cpd-8N-((4-((((S)-l,4-dioxan-2-yl)methyl)amino)-3- 925nitrophenyl)sulfonyl)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-((S)-3-methyl-2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)benzamide Cpd-94-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′- 943biphenyl]-2-yl)methyl)piperazin-l-yl)-N-((4-((((S)-2-fluoro-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((S)-3-methyl-2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)benzamide Cpd-104-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′- 943biphenyl]-2-yl)methyl)piperazin-l-yl)-N-((4-((((R)-2-fluoro-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((S)-3-methyl-2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][l,4]oxazin- 1(6H)-yl)benzamideCpd-11 (R)-N-((4-(((l,4-dioxan-2-yl)methyl)amino)-3- 911nitrophenyl)sulfonyl)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][l,4]oxazin-1(6H)-yl)benzamide Cpd-12 (S)-N-((4-(((l,4-dioxan-2-yl)methyl)amino)-3-911 nitrophenyl)sulfonyl)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][l,4]oxazin-1(6H)-yl)benzamide Cpd-13(S)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro- 929[1,1′-biphenyl]-2-yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][l,4]oxazin- 1(6H)-yl)-N-((4-(((2-fluoro-l,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide Cpd-14(R)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro- 929[1,1′-biphenyl]-2-yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][l,4]oxazin-1(6H)-yl)-N-((4-(((2-fluoro-l,4- dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide Cpd-15(R)-N-((4-(((l,4-dioxan-2-yl)methyl)amino)-3- 947nitrophenyl)sulfonyl)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,3-difluoro-2,3- dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)benzamide Cpd-16(S)-N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3- 947nitrophenyl)sulfonyl)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,3-difluoro-2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)benzamide Cpd-17(S)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro- 965[1,1′-biphenyl]-2-yl)methyl)piperazin-l-yl)-2-(3,3-difluoro-2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][l,4]oxazin-1(6H)-yl)-N-((4-(((2- fluoro-l,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide Cpd-18(R)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro- 965[1,1′-biphenyl]-2-yl)methyl)piperazin-l-yl)-2-(3,3-difluoro-2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][l,4]oxazin-1(6H)-yl)-N-((4-(((2-fluoro-l,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide Cpd-194-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′- 945biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,3-difluoro-2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][l,4]oxazin-1(6H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide Cpd-204-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′- 945biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,3-difluoro-2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide

Biological Example 1: Bcl-2 Competition Binding (FluorescencePolarization) Assay

The fluorescence-labeled 23 amino acid peptide BH3 was purchased fromCalBiochem (NLWAAQRYGRELRRMSDKFVD). An unbound Fluorescein labeled BH3peptide emits random light with respect to the plane of polarizationplane of excited light, resulting in a lower polarization degree (mP)value. When the peptide is bound to Bcl-2, the complex tumble slower andthe emitted light can have a higher level of polarization, resulting ina higher mP value. This binding assay was performed in 96-well plate andwith each assay contained 15 and 30 nM of labeled peptide and purifiedBcl-2 protein (purchased from R&D Systems, Inc). The assay buffercontained 20 mM Hepes (pH 7.0), 50 mM KCl, 5 mM MgCl₂, 20 mM Na₂MoO₄,0.1 mg/ml Bovine Gamma Globulin and 0.01% NP40. Compounds were dilutedin DMSO and added to the final assay with concentration range from 20 μMto 2 nM. The polarization degree (mP) value was determined by BioTekSynergy II with background subtraction after 3 hours of incubation atroom temperature. IC₅₀ was calculated using Prism software withsigmoidal dose-response curve fitting. ABT-737 was used as referencecompound. Such assays, carried out with a range of doses of testcompounds, allowed the determination of an approximate IC₅₀ value.Although the inhibitory properties of the compounds of the presentinvention vary with structural change as expected, the activitygenerally exhibited by these agents was in the range of IC₅₀=0.1-1000nM.

Biological Example 2: In Vitro Anti-Proliferation Assay inBCL-2-Dependent Acute Lymphoblastic Leukemia (ALL) Cell Line RS4;11

Cell antiproliferation was assayed by PerkinElmer ATPlite™ LuminescenceAssay System. Briefly, the various test cancer cell lines were plated ata density of about 1×10⁴ cells per well in Costar 96-well plates, andwere incubated with different concentrations of compounds for about 72hours in medium supplemented with 5% FBS or 10% normal human serum(NHS). One lyophilized substrate solution vial was then reconstituted byadding 5 mL of substrate buffer solution, and was agitated gently untilthe solution is homogeneous. About 50 μL of mammalian cell lysissolution was added to 100 μL of cell suspension per well of amicroplate, and the plate was shaken for about five minutes in anorbital shaker at ˜700 rpm. This procedure was used to lyse the cellsand to stabilize the ATP. Next, 50 μL substrate solution was added tothe wells and microplate was shaken for five minutes in an orbitalshaker at ˜700 rpm. Finally, the luminescence was measured by aPerkinElmer TopCount® Microplate Scintillation Counter. Such assays,carried out with a range of doses of test compounds, allowed thedetermination of the cellular anti-antiproliferative IC₅₀ of thecompounds of the present invention. The following table lists the IC50values of certain compounds of the invention. As shown below, Example 3is significantly more potent than both NW-4-8 (Example 2) as well asABT-199.

Compound IC50, RS4;11 5% FBS ABT-199 5.5 nM Example 12 in WO/2017/13247415.8 nM  Example 2 (NW-4-8) 4.8 nM Example 3 2.6 nM

The following table lists the IC₅₀ values of another study for certaincompounds of the invention.

Compound IC50, RS4; 115% FBS ABT-199 9.2 nM Example 3 1.4 nM Example 6(S, assumed) 3.2 nM Example 6 (R, assumed) 1.3 nM Example 7 5.6 nM

The following table lists the IC₅₀ values of another study for certaincompounds of the invention.

Compound IC50, RS4; 115% FBS ABT-199 4.7 nM Example10 3.1 nM

Biological Example 3: In Vitro Anti-Proliferation Assay inBCL-XL-Dependent Lines Small Cell Lung Cancer (SCLC) Cell Line H146

Cell antiproliferation was assayed by PerkinElmer ATPlite™ LuminescenceAssay System. Briefly, the various test cancer cell lines were plated ata density of about 1×10⁴ cells per well in Costar 96-well plates, andwere incubated with different concentrations of compounds for about 72hours in medium supplemented with 5% FBS. One lyophilized substratesolution vial was then reconstituted by adding 5 mL of substrate buffersolution, and was agitated gently until the solution was homogeneous.About 50 μL of mammalian cell lysis solution was added to 100 μL of cellsuspension per well of a microplate, and the plate was shaken for aboutfive minutes in an orbital shaker at ˜700 rpm. This procedure is used tolyse the cells and to stabilize the ATP. Next, 50 μL substrate solutionwas added to the wells and microplate was shaken for five minutes in anorbital shaker at ˜700 rpm. Finally, the luminescence was measured by aPerkinElmer TopCount® Microplate Scintillation Counter. Such assays,carried out with a range of doses of test compounds, allow thedetermination of the cellular anti-antiproliferative IC₅₀ of thecompounds of the present invention.

Biological Example 4: Mice PK Study

The pharmacokinetics of compounds were evaluated in CD-1 mouse viaIntravenous and Oral Administration. The IV dose was administered as aslow bolus in the Jugular vein, and oral doses were administered bygavage. The formulation for IV dosing is 5% DMSO in 20% HPBCD in water,and the PO formulation is 2.5% DMSO, 10% EtOH, 20% Cremphor EL, 67.5%D5W. The PK time point for the IV arm was 5, 15, 30 min, 1, 2, 4, 6, 8,12, 24 hours post dose, and for PO arm was 15, 30 min, 1, 2, 4, 6, 8,12, 24 hours post dose. Approximately 0.03 mL blood was collected ateach time point. Blood of each sample was transferred into plastic microcentrifuge tubes containing EDTA-K2 and plasma was collected within 15min by centrifugation at 4000 g for 5 minutes in a 4′C centrifuge.Plasma samples were stored in polypropylene tubes. The samples werestored in a freezer at −75±15° C. prior to analysis. Concentrations ofcompounds in the plasma samples were analyzed using a LC-MS/MS method.WinNonlin (Phoenix™, version 6.1) or other similar software was used forpharmacokinetic calculations. The following pharmacokinetic parameterswere calculated, whenever possible from the plasma concentration versustime data: IV administration: C₀, CL, V_(d), Tin, AUC_(inf), AUC_(last),MRT, Number of Points for Regression; PO administration: C_(max),T_(max), T_(1/2), AUC_(inf), AUC_(last), F %, Number of Points forRegression. The pharmacokinetic data was described using descriptivestatistics such as mean, standard deviation. Additional pharmacokineticor statistical analysis was performed at the discretion of thecontributing scientist, and was documented in the data summary. The PKresults of oral dosing of po, 10 mg/kg is shown in the Table below. Asshown below, many compounds have significantly better PK than NW-4-8(Example 2), see AUC and/or bioavailability values.

Compound AUC(h * ng/mL) t^(1/2) (hour) Bioavailabilty Example 2 (NW-4-8)10,365 2.7 68% Example 6 (S) 12,068 74% Example 6 (R) 16,114 3.2 Example7 10,972 3.2 90% Example 9 19,922 4.1 Example 10 34,982 4.1 78%

For comparison purpose, the PK results or oral dosing of po, 10 mg/kg ofcertain compounds in WO/2017/132474 were obtained using the same methodsand shown in the Table below.

Compound AUC (h * ng/mL) Example 12 in WO/2017/132474 1,088 Example 16in WO/2017/132474 849 Example 18 in WO/2017/132474 1,890

Biological Example 5: In Vivo Xenograft Studies

Compound of Example 3 was selected for in vivo studies in theBCL-2-dependent acute lymphoblastic leukemia RS4;11 xenograft model. TheCB.17 SCID mice were obtained at age 6-8 weeks from vendors andacclimated for a minimum 7-day period. The cancer cells were thenimplanted into the nude mice. Depending on the specific tumor type,tumors were typically detectable about two weeks following implantation.When tumor sizes reached ˜100-200 mm³, the animals with appreciabletumor size and shape were randomly assigned into groups of 8 mice each,including one vehicle control group and treatment groups. Dosing variesdepending on the purpose and length of each study, which typicallyproceeded for about 3-4 weeks. Tumor sizes and body weight weretypically measured three times per week. In addition to thedetermination of tumor size changes, the last tumor measurement was usedto generate the tumor size change ratio (T/C value), a standard metricdeveloped by the National Cancer Institute for xenograft tumorevaluation. In most cases, % T/C values were calculated using thefollowing formula: % T/C=100×ΔT/ΔC if ΔT>0. When tumor regressionoccurred (ΔT<0), however, the following formula was used: %T/T0=100×ΔT/T0. Values of <42% were considered significant.

As shown below, 7 doses of Example 3 compound produced dose-dependentreduction of tumor growth. At 100 mg/kg, Example 3 compound led tocomplete regression of the tumor at day 18.

BW Tumor Group mice Agent mg/kg Route Schedule Nadir volume 1 8 vehicleVehicle po qd × 7 −2.10% 1124 mm³   2 8 Example 3 25 po qd × 7 −3.60%368 mm³  3 8 Example 3 50 po qd × 7 −2.90% 26 mm³  4 8 Example 3 100 poqd × 7 −2.10% 0 mm³ 5 8 ABT-199 50 po qd × 7 −3.60% 0 mm³

As shown below, Example 10 compound also produced dose-dependentreduction of tumor growth. At 50 mg/kg, Example 10 compound led toregression of the tumor at day 19.

Tumor Group mice Agent mg/kg Route Schedule volume 1 8 vehicle Vehiclepo qd × 21 983.6 mm³  2 8 Example 10 12.5 po qd × 21  295 mm³ 3 8Example 10 25 po qd × 21 47.4 mm³ 4 8 Example 10 50 po qd × 21 32.0 mm³5 8 ABT-199 50 po qd × 21 17.4 mm³

1. A compound of Formula (A), or an N-oxide thereof, or apharmaceutically acceptable salt, solvate, polymorph, tautomer,stereoisomer, an isotopic form, or a prodrug of said compound of Formula(A) or N-oxide thereof:

wherein Q₁ is a 6-membered heterocycloalkyl, 6-memberedheterocycloalkenyl, or 6-membered heteroaryl; Q₂ is an aryl orheteroaryl; Q₃ is a cycloalkyl, cycloalkenyl, heterocycloalkyl,heterocycloalkenyl, aryl, or heteroaryl; Q₄ is

each of R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, and R₁₂,independently, is H, D, alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl,halo, nitro, oxo, cyano, OR_(a), SR_(a), alkyl-R_(a), NH(CH₂)_(p)R_(a),C(O)R_(a), S(O)R_(a), SO₂R_(a), C(O)OR_(a), OC(O)R_(a), NR_(b)R_(c),P(O)R_(b)R_(c), alkyl-P(O)R_(b)R_(c), C(O)N(R_(b))R_(c),N(R_(b))C(O)R_(c), S(O)(═N(R_(a)))R_(b), —N═S(O)R_(b)R_(c),SO₂N(R_(b))R_(c), or N(R_(b))SO₂R_(c), in which said cycloalkyl,cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl isoptionally substituted with one or more R_(d); R_(a), R_(b), R_(c) andR_(d), independently, is H, D, alkyl, alkenyl, alkynyl, halo, cyano,amine, nitro, hydroxy, C(O)NHOH, C(O)OH, C(O)NH₂, alkoxy, alkoxyalkyl,haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl,alkylcarbonylamino, alkylamino, oxo, halo-alkylamino, cycloalkyl,cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl,in which said alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl,heterocycloalkenyl, aryl, heteroaryl is optionally substituted with oneor more R_(e); R_(e) is H, D, alkyl, alkenyl, alkynyl, halo, cyano,amine, nitro, hydroxy, C(O)NHOH, alkoxy, alkoxyalkyl, haloalkyl,hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl,alkylcarbonylamino, alkylamino, oxo, halo-alkylamino, cycloalkyl,cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl;Z₁ is a bond, (CH₂)_(p), N(H), O, S, C(O), S(O₂), OC(O), C(O)O, OSO₂,S(O₂)O, C(O)S, SC(O), C(O)C(O), C(O)N(H), N(H)C(O), S(O₂)N(H),N(H)S(O₂), OC(O)O, OC(O)S, OC(O)N(H), N(H)C(O)O, N(H)C(O)S,N(H)C(O)N(H), (CH₂)_(p)N(H)(CH₂)_(q), (CH₂)_(p)N(H)C(O)(CH₂)_(q),(CH₂)_(p)C(O)N(H)(CH₂)_(q), OC(O)N(H)(CH₂)_(p+1)N(H)(CH₂)_(q), abivalent alkenyl group, or a bivalent alkynyl group; L is a bond, alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl,heterocycloalkenyl, aryl, or heteroaryl, in which said alkyl,cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, orheteroaryl is optionally substituted with one or more R_(d); each of Y,W, and W₂, independently, is CH or N; W₁ is N; W₃ is O or N(R_(a)); V isN, C, or CH; two of R₉ group, taken together with the atom to which theyare attached, may optionally form a cycloalkyl or heterocycloalkyl, inwhich said cycloalkyl or heterocycloalkyl of R₉ is optionallysubstituted with one or more R_(d); two of R₂ group, taken together withthe atom to which they are attached, may optionally form a cycloalkyl orheterocycloalkyl, in which said cycloalkyl or heterocycloalkyl of R₂ isoptionally substituted with one or more R_(d); two of R₁₀ group, takentogether with the atom to which they are attached, may optionally form acycloalkyl or heterocycloalkyl, in which said cycloalkyl orheterocycloalkyl of R₁₀ is optionally substituted with one or moreR_(d); R₁₁ and R₁₂ group, taken together with the atom to which they areattached, may optionally form a cycloalkyl or heterocycloalkyl, in whichsaid cycloalkyl or heterocycloalkyl of R₁₁ or R₁₂ is optionallysubstituted with one or more R_(d); R₁₀ and R₂group, taken together withthe atom to which they are attached, may optionally form a cycloalkyl orheterocycloalkyl, in which said cycloalkyl or heterocycloalkyl of R₁₀ orR₂ is optionally substituted with one or more R_(d); R₄ and —Z₁-L-R₆group, taken together with the atom to which they are attached, mayoptionally form a cycloalkyl, cycloalkenyl, heterocycloalkyl,heterocycloalkenyl, aryl, or heteroaryl, in which said cycloalkyl,cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroarylof R₄ is optionally substituted with one or more R_(d); R_(b) and R_(c)group, taken together with the atom to which they are attached, mayoptionally form a cycloalkyl, or heterocycloalkyl, in which saidcycloalkyl or heterocycloalkyl of R_(b) and R_(c), is optionallysubstituted with one or more R_(e); two of R_(d) group, taken togetherwith the atom to which they are attached, may optionally form acycloalkyl, or heterocycloalkyl, in which said cycloalkyl orheterocycloalkyl of R_(d) is optionally substituted with one or moreR_(e); two of R_(e) group, taken together with the atom to which theyare attached, may optionally form a cycloalkyl, or heterocycloalkyl;each of j and k, independently, is 0, 1, 2, 3, 4, 5, 6, 7, or 8; andeach of m, n, p, q, and r, independently, is 0, 1, 2, 3, or 4;optionally, provided that when

 then —Z₁-L-R₆ is not


2. The compound according to claim 1 or an N-oxide thereof, or apharmaceutically acceptable salt, solvate, polymorph, tautomer,stereoisomer, an isotopic form, or a prodrug thereof, wherein thecompound is represented by Formula (B):

wherein Z₂ is —O—, —CH₂—, —C(O)—, —N(R_(a))—, —S—, —S(O)—, —S(O₂)—,—S(O)(═N(R_(a)))—, —P(O)(R_(a))—; wherein R_(a) of Z₂, independently, isH, D, C₁-C₆alkyl, C₂-C₆alkenyl, C₁-C₆alkylcarbonyl, C₁-C₆alkoxycarbonyl,C₃-C₆cycloalkyl, 5-8 membered monocyclic heterocycloalkyl, C₆-C₁₄aryl,or 5-8 membered monocyclicheteroaryl, in which said C₁-C₆alkyl,C₃-C₆cycloalkyl, 5-8 membered monocyclic heterocycloalkyl, C₆-C₁₄aryl,5-8 membered monocyclic heteroaryl is optionally substituted with one ormore Re, and A is —(CR₂R₂)_(r)— or —O—; wherein r is 0, 1, 2, or 3; eachR₂ independently is H, —(C₁-C₄)alkoxy, —(C₁-C₄)alkyl optionallysubstituted with —(C₁-C₄)alkoxy, or two of R₂ groups, taken togetherwith the same carbon atom to which they are attached, form—(C₃-C₆)cycloalkyl or 4-6 membered heterocyclic ring, wherein the—(C₃-C₆)cycloalkyl or 4-6 membered heterocyclic ring is optionallysubstituted with —(C₁-C₄)alkyl, —(C₁-C₄)haloalkyl or oxetanyl.
 3. Thecompound according to claim 2 or an N-oxide thereof, or apharmaceutically acceptable salt, solvate, polymorph, tautomer,stereoisomer, an isotopic form, or a prodrug thereof, wherein thecompound is represented by Formula (C):

wherein R₁ is H, D, halo or —(C₁-C₄)alkyl.
 4. The compound according toclaim 3 or an N-oxide thereof, or a pharmaceutically acceptable salt,solvate, polymorph, tautomer, stereoisomer, an isotopic form, or aprodrug thereof, wherein the compound is represented by Formula (D):

wherein R₅ independently, is nitro, halo, or —SO₂R_(a), wherein R_(a) ofR₅ is —(C₁-C₄)alkyl or —(C₁-C₄)haloalkyl; Z₁ is absent, NH,N(H)(CH₂)_(q), O, S, or —(C₁-C₄)alkylene, wherein q is 1, 2, or 3; L isabsent or —(C₁-C₄)alkylene optionally substituted with—(C₃-C₆)cycloalkyl; and R₆ is H, D,—N(CH₃)—(C₁-C₄)alkylene-P(Ox(C₁-C₄)alkoxy)₂, —P(O)(N(CH₃)₂)(OEt),—P(O)(O—(C₁-C₄)alkylene-O—CO—(C₁-C₄)alkyl)₂, —(C₃-C₆)cycloalkyl, phenyl,5-7 membered heterocyclyl, 8-10 membered bicyclic ring, wherein the—(C₃-C₆)cycloalkyl, phenyl, 5-7 membered heterocyclyl, or 7-10 memberedbicyclic ring is optionally substituted with halo, —OH, —CN, —COOH,—NH₂, —N(CH₃)₂, —(C₁-C₄)alkyl, —(C₁-C₄)alkoxy, cyclopropyl, 4-6 memberedheterocyclyl, —CH₂P(O)(OH)₂, —CH₂P(O)((C₁-C₄)alkoxy)₂,—P(O)((C₁-C₄)alkyl)₂ or —N═S(Ox(C₁-C₄)alkyl)₂.
 5. The compound accordingto claim 4 or an N-oxide thereof, or a pharmaceutically acceptable salt,solvate, polymorph, tautomer, stereoisomer, an isotopic form, or aprodrug thereof, wherein R₉ independently, is D, halo, —OH, CN, —NH₂,═O, —(C₁-C₄)alkyl, —(C₁-C₄)alkoxy, —(C₁-C₄)haloalkyl,—(C₁-C₄)hydroxyalkyl, —(C₃-C₆)cycloalkyl, or 1,3-dithiolanyl; and k is0, 1, 2, 3, or
 4. 6. The compound according to claim 5 or an N-oxidethereof, or a pharmaceutically acceptable salt, solvate, polymorph,tautomer, stereoisomer, an isotopic form, or a prodrug thereof, whereinA is —CH₂- or —O-.
 7. The compound according to claim 6 or an N-oxidethereof, or a pharmaceutically acceptable salt, solvate, polymorph,tautomer, stereoisomer, an isotopic form, or a prodrug thereof, whereineach R₂ independently is —CH₃; and n is 0 or
 2. 8. The compoundaccording to claim 7 or an N-oxide thereof, or a pharmaceuticallyacceptable salt, solvate, polymorph, tautomer, stereoisomer, an isotopicform, or a prodrug thereof, wherein Z₂ is —O-.
 9. The compound accordingto claim 8 or an N-oxide thereof, or a pharmaceutically acceptable salt,solvate, polymorph, tautomer, stereoisomer, an isotopic form, or aprodrug thereof, wherein R₁ is Cl.
 10. The compound according to claim 9or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate,polymorph, tautomer, stereoisomer, an isotopic form, or a prodrugthereof, wherein R₅ is nitro.
 11. The compound according to claim 10 oran N-oxide thereof, or a pharmaceutically acceptable salt, solvate,polymorph, tautomer, stereoisomer, an isotopic form, or a prodrugthereof, wherein Z₁ is absent, NH or O.
 12. The compound according toclaim 11 or an N-oxide thereof, or a pharmaceutically acceptable salt,solvate, polymorph, tautomer, stereoisomer, an isotopic form, or aprodrug thereof, wherein Z₂ is —O—, —CH₂—, —C(O)—, —NH—, —N-(oxetanyl)-,—S—, —S(O)—, —S(O₂)—, —S(O)(═NH)—, —S(O)(═NCH₃)—, or —P(O)(CH₃)—. 13.The compound according to claim 12 or an N-oxide thereof, or apharmaceutically acceptable salt, solvate, polymorph, tautomer,stereoisomer, an isotopic form, or a prodrug thereof, wherein R₆ is H,D, —(C₃-C₆)cycloalkyl, phenyl, tetrahydro-2H-pyranyl, or 1,4-dioxanyl,wherein the —(C₃-C₆)cycloalkyl, phenyl, tetrahydro-2H-pyranyl or1,4-dioxanyl is optionally substituted with 1 or 2 groups selected fromhalogen, —OH, ═O, —(C₁-C₄)alkyl, or —(C₁-C₄)alkoxy.
 14. The compoundaccording to claim 13 or an N-oxide thereof, or a pharmaceuticallyacceptable salt, solvate, polymorph, tautomer, stereoisomer, an isotopicform, or a prodrug thereof, wherein R₆ is tetrahydro-2H-pyranyl or1,4-dioxanyl, wherein the tetrahydro-2H-pyranyl or 1,4-dioxanyl isoptionally substituted with 1 or 2 groups selected from halogen.
 15. Thecompound according to claim 1 or an N-oxide thereof, or apharmaceutically acceptable salt, solvate, polymorph, tautomer,stereoisomer, an isotopic form, or a prodrug thereof, wherein thecompound is(R)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3-methyl-2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,(S)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3-methyl-2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,(R)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2-methyl-2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]thiazin-1(6H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,(R)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2-(3-(trifluoromethyl)-2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)benzamide,(R)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2-(3-(trifluoromethyl)-2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]thiazin-1(6H)-yl)benzamide,4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,(R)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-(2-methyl-2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)benzamide,4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,2-dimethyl-2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,(R)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-(3-methyl-2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)benzamide,(S)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-(3-methyl-2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)benzamide,(S)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2-methyl-2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(4,4-dioxido-2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]thiazin-1(6H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,(S)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2-(3-(trifluoromethyl)-2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)benzamide,(S)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2-(3-(trifluoromethyl)-2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]thiazin-1(6H)-yl)benzamide,4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl-2,2,3,3-d4)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,(S)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-(2-methyl-2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)benzamide,4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,3-dimethyl-2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,N-((4-((((R)-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-((S)-3-methyl-2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)benzamide,4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((((S)-2-fluoro-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((S)-3-methyl-2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)benzamide,(R)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)benzamide,(S)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((4-(((2-fluoro-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,(R)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,3-difluoro-2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)benzamide,(S)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,3-difluoro-2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((4-(((2-fluoro-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,3-difluoro-2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,N-((4-((((S)-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-((S)-3-methyl-2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)benzamide,4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((((R)-2-fluoro-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((S)-3-methyl-2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)benzamide,(S)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)benzamide,(R)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((4-(((2-fluoro-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,(S)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,3-difluoro-2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)benzamide,(R)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,3-difluoro-2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((4-(((2-fluoro-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,or4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,3-difluoro-2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide.16. A pharmaceutical composition comprising a compound of Formula (A) oran N-oxide thereof as defined in claim 1, or a pharmaceuticallyacceptable salt, solvate, polymorph, tautomer, stereoisomer, an isotopicform, or a prodrug of said compound of Formula (A) or an N-oxidethereof, and a pharmaceutically acceptable diluent or carrier.
 17. Amethod of treating a neoplastic disease, an autoimmune disease, or aneorodegenerative disease, comprising administering to a subject in needthereof an effective amount of a compound of Formula (A) or an N-oxidethereof as defined in claim 1, or a pharmaceutically acceptable salt,solvate, polymorph, tautomer, stereoisomer, an isotopic form, or aprodrug of said compound of Formula (A) or an N-oxide thereof.
 18. Themethod of claim 17, wherein the neoplastic disease, the autoimmunedisease, or the neorodegenerative disease is characterized by abnormal(e.g., enhanced or increased) Bcl-2 activity, such as a hematologicalmalignancy/cancer, type I diabetes, or schizophrenia.
 19. The method ofclaim 17, wherein the neoplastic disease is myeloma, multiple myeloma,lymphoma, follicular lymphoma (FL), non-Hodgkin's lymphoma, leukemia,acute leukemia, acute lymphoblastic leukemia (ALL) (such asBCL-2-dependent ALL and pediatric ALL), chronic lymphoblastic leukemia(CLL) (such as relapsed/refractory CLL, del(17p) CLL), chronic myeloidleukemia (CML) (such as blast-crisis CML), mantle cell lymphoma (MCL),diffuse large B-cell lymphoma, lung cancer such as small cell lungcancer (SCLC), melanoma, breast cancer, or prostate cancer, includingdrug-resistant cancer thereof.
 20. The method of claim 17, furthercomprising administering one or more further treatment(s) effective totreat the neoplastic disease, such as surgery, radiation therapy, achemotherapeutic agent (such as bendamustine, NL-101, cisplatin,carboplatin, etoposide, topotecan), a target therapy (such as rituximab,ibrutinib, ACP-196, idelalisib); an antibody-drug conjugate or ADC (suchas brentuximab vedotin), an immunotherapy (such as pembrolizumab,nivolumab, atezolizumab, durvalumab, avelumab), or a CAR-T therapy (suchas tisagenlecleucel, axicabtagene ciloleucel).